DK163918B - CYCLOPROPANCARBOXYLIC ACID DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND PESTICIDE PREPARATIONS WITH CONTENTS - Google Patents
CYCLOPROPANCARBOXYLIC ACID DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND PESTICIDE PREPARATIONS WITH CONTENTS Download PDFInfo
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- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/743—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of acids with a three-membered ring and with unsaturation outside the ring
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- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
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- A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
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- C07C69/74—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring
- C07C69/743—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring of acids with a three-membered ring and with unsaturation outside the ring
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
- C07D213/647—One oxygen atom attached in position 2 or 6 and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters
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- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
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Abstract
Description
iin
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Opfindelsen angår hidtil ukendte cyclopropancarboxyl-syrederivater med den i krav 1 angivne formel I, deres fremstilling og pesticide præparater med indhold deraf.The invention relates to novel cyclopropane carboxylic acid derivatives of the formula I as defined in claim 1, their preparation and pesticidal compositions containing them.
Opfindelsen angår cyclopropancarboxylsyrederivater, 5 der i 3-stillingen har en umættet sidekæde med Z-geometri og med strukturen H-\ .c— C ^ 10 ^2° ^The invention relates to cyclopropane carboxylic acid derivatives having at the 3-position an unsaturated side-chain of Z-geometry and of the structure H - C
Man kendte i forvejen ganske vist cyclopropancarbox-ylsyrederivater med, i 3-stillingen, en kæde med strukturen H.Cyclopropane carboxylic acid derivatives were already known to have, at the 3-position, a chain of structure H.
15 \ / g------- —o / \ R02c η men hvis geometri i hovedsagen er E. F.eks. kan nævnes 20 fransk patentskrift nr. 2.185.612 samt tidsskrift J. Chem.15 \ / g ------- —o / \ R02c η but whose geometry is essentially E. For example. may be mentioned 20 French Patent No. 2,185,612 and the journal J. Chem.
Soc. Perkin I, side 2470, 1974 og Pest. Sci. 1_, side 499, 1976. Imidlertid er sidekædegeometrien af disse forbindelser overvejende E. I virkeligheden fører de syntesefremgangsmåder, som benyttes til fremstillingen af disse deri-25 vater, næsten kun til E-geometrien {se Agr. Biol. Chem. 34, side 1119 1970). For disse forbindelser, hvis geometri i sidekæden er E, har man ikke kunnet påvise nogen bemærkelsesværdig egenskab.Soc. Perkin I, pages 2470, 1974 and Pest. Sci. 1, page 499, 1976. However, the side chain geometry of these compounds is predominantly E. In fact, the synthetic methods used to prepare these derivatives lead almost exclusively to the E geometry {see Agr. Biol. Chem. 34, page 1119 1970). For these compounds, whose geometry in the side chain is E, no remarkable property has been demonstrated.
Det har nu vist sig, at forbindelserne med formlen 30 I, hvis sidekæde har Z-struktur, udviser særdeles gode in-sekticide egenskaber, jf. sammenligningseksempler i den eksperimentelle del nedenfor.It has now been found that the compounds of formula 30 I, whose side chain has Z structure, exhibit very good in-secticidal properties, cf. comparative examples in the experimental part below.
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2 52 5
Opfindelsen angår især de forbindelser, hvis fremstilling er anført i den eksperimentelle del. Blandt disse 10 forbindelser skal især nævnes: - (lR,cis)-2,2-dimethyl-3-((Z)-3-methoxy-3-oxo-l-propenyl)--cyclopropancarboxylsyre =(lS)-2 -me thy 1-4 -oxo-3-( 2-prope -nyl)-2-cyclopenten-l-ylester, - (lR,cis)-2,2-dimethy1-3-((Z)-3-tert.-butoxy-3-oxo-l-prope- 15 nyl) -cy clopropancarboxylsyre -l-(3fpropargyl-2,5 -dioxoimid a- zolidinyl)-methylester, (IR, cis)-2,2-dimethyl-3-( (Z)-2-cyclopropylmethoxycarbonyl-ethenyl)-cyclopropancarboxylsyre-l-(3*-propargyl-2,5-dioxo-imidazolidinyl)-methylester, 20 - (lR,cis)-2,2-dimethyl-3-((Z)-2-isopropoxycarbonylethenyl)--cyclopropancarboxylsyre-l-(R)-3-phenoxyphenylethylester, - (lR,cis)-2,2-dimethyl-3-((Z)-2-isopropoxycarbonylethenyl)-, -cyclopropancarboxylsyre-l-(3-propargyl-2,5-dioxoimidazoli-dinyl)-methylester og 25 - (IR, trans)-2,2-dimethyl-3-((Z)-2-isopropoxycarbonylethenyl)- -cyclopropan-l-(R)-3-phenoxyphenylethylester.The invention relates in particular to the compounds whose preparation is set forth in the experimental part. In particular, among these 10 compounds are mentioned: - (1R, cis) -2,2-dimethyl-3 - ((Z) -3-methoxy-3-oxo-1-propenyl) - cyclopropane carboxylic acid = (1S) -2 - with thy 1-4-oxo-3- (2-prope-nyl) -2-cyclopenten-1-yl ester, - (1R, cis) -2,2-dimethyl-3 - ((Z) -3-tert. -butoxy-3-oxo-1-propanyl) -cyclopropane carboxylic acid 1- (3-propargyl-2,5-dioxoimide-azolidinyl) methyl ester, (IR, cis) -2,2-dimethyl-3- ( (Z) -2-cyclopropylmethoxycarbonyl-ethenyl) -cyclopropane carboxylic acid 1- (3 * -propargyl-2,5-dioxo-imidazolidinyl) methyl ester, 20 - (1R, cis) -2,2-dimethyl-3 - (( Z) -2-isopropoxycarbonylethenyl) - cyclopropane carboxylic acid 1- (R) -3-phenoxyphenylethyl ester, - (1R, cis) -2,2-dimethyl-3 - ((Z) -2-isopropoxycarbonylethenyl) -, cyclopropane carboxylic acid 1- (3-propargyl-2,5-dioxoimidazolidinyl) methyl ester and 25 - (IR, trans) -2,2-dimethyl-3 - ((Z) -2-isopropoxycarbonylethenyl) -cyclopropane-1- R) -3-phenoxyphenylethylester.
Forbindelserne med formlen I har interessante egenskaber, som muliggør deres anvendelse ved bekæmpelsen af parasitter. Det kan f.eks. dreje sig om bekæmpelse af planters pa-30 rasitter, parasitter i husholdningen og parasitter på varmblodede dyr. Således kan man benytte forbindelserne ifølge opfindelsen til bekæmpelse af insekter, nematoder og acarider, som er parasitter på planter og dyr.The compounds of formula I have interesting properties which enable their use in the control of parasites. It can for example. These include the control of plants' parasites, domestic parasites and parasites on warm-blooded animals. Thus, the compounds of the invention can be used to control insects, nematodes and acarides which are parasites on plants and animals.
Gennem opfindelsen muliggøres anvendelsen af forbin-35 delserne med formlen I defineret som ovenfor til bekæmpelse af parasitter på planter, parasitter i husholdningen og parasitter på varmblodede dyr.The invention enables the use of the compounds of formula I as defined above to control parasites on plants, domestic parasites and parasites on warm-blooded animals.
Forbindelserne med formlen I kan altså benyttes tilThe compounds of formula I can thus be used for
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3 navnlig bekæmpelse af insekter i landbruget, til bekæmpelse af f.eks. bladlus, laiver af lepidopterer og coleopterer.3, in particular, the control of insects in agriculture, for the control of e.g. aphids, lepidopterous and coleopteric larvae.
De benyttes i doser på 10-300 g aktivt stof pr. ha.They are used in doses of 10-300 g of active substance per day. ha.
Forbindelserne med formlen I kan ligeledes benyttes 5 til bekæmpelse af insekter i husholdningen, navnlig fluer, myg og kakerlakker.The compounds of formula I can also be used to control domestic insects, especially flies, mosquitoes and cockroaches.
Visse af forbindelserne med formlen I har navnlig en udmærket knock-down-virkning.In particular, some of the compounds of formula I have an excellent knock-down effect.
Forbindelsen ifølge eksempel 1 er særlig bemærkelses - 10 værdig.The compound of Example 1 is particularly noteworthy.
Forbindelsen med formlen I er desuden lysstabile og er ikke giftige for pattedyr.In addition, the compound of formula I is light stable and is not toxic to mammals.
Kombinationen af disse egenskaber gør forbindelserne med formlen I til forbindelser, som svarer helt til kravene 15 i den moderne agrokemiske industri. De gør det muligt at beskytte afgrøderne under bevarelse af omgivelserne.The combination of these properties makes the compounds of formula I into compounds which fully meet the requirements of 15 in the modern agrochemical industry. They enable the crops to be protected while preserving the environment.
Forbindelserne med formlen I kan også benyttes til bekæmpelse af acarider og nematoder, som er parasitter på planter.The compounds of formula I can also be used to control acarides and nematodes which are parasites on plants.
20 Forbinde Is eme med formlen I kan yderligere benyttes til bekæmpelse af acarider, som er parasitter på dyr, til bekæmpelse af f.eks. blodmider og navnlig blodmider af arten Boophilus, arten Hyalomnia, arten Imblyomnia og arten Rhipi-cephalus eller til bekæmpelse af alle slags skab og navnlig 25 sarcoptisk, psoroptisk og chorioptisk skab.The compound of formula I can further be used to control acarides which are parasites on animals, to control e.g. blood mites and in particular blood mites of the species Boophilus, the species Hyalomnia, the species Imblyomnia and the species Rhipi-cephalus or to combat all kinds of enclosures and in particular 25 sarcoptic, psoroptic and chorioptic enclosures.
Opfindelsen angår således ligeledes anvisningen af præparater beregnet til bekæmpelsen af parasitter på varmblodede dyr, parasitter i husholdningen og parasitter på planter og indeholdende i det mindste én af de ovenfor omhandlede for-30 bindeiser.The invention thus also relates to the provision of compositions intended for the control of parasites on warm-blooded animals, domestic parasites and parasites on plants and containing at least one of the above-mentioned binding claims.
Specielt anvises insekticide præparater med i det mindste en af de omhandlede forbindelser som aktiv bestanddel.In particular, insecticidal compositions with at least one of the compounds of this invention are designated as active ingredient.
Specielt anvises præparater, der som aktiv bestanddel indeholder: 35 - (lR,cis)-2,2*-dimethyl-3-((Z)-3-methoxy-3-oxo-l-propenyl)- -cyelopropancarboxylsyre-(lS)-2-methyl-4-oxo-3-(2-propenyl)- -2-cyclopenten-l-ylster, - (lR,cis)-2,2-dimethyl-3-((Z)-3-tert.-butoxy-3-oxo-l-propenyl)~Specifically, compositions containing as active ingredient are disclosed: 35 - (1R, cis) -2,2 * -dimethyl-3 - ((Z) -3-methoxy-3-oxo-1-propenyl) -cyelopropanecarboxylic acid (1S) ) -2-methyl-4-oxo-3- (2-propenyl) -2-cyclopenten-1-ylster, - (1R, cis) -2,2-dimethyl-3 - ((Z) -3-tert .-butoxy-3-oxo-l-propenyl) ~
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4 -cyclopropancarboxylsyre-l-(3-propargyl-2,5-dioxoimidazo- lidinyl)-methylester, - (IR,cis)-2,2-dime thy1-3-((2)-2-cyclopropylme thoxycarboxy1-e thenyl)-cyclopropancarboxylsyre-1-(3-propargyl-2,5-dioxo - 5 imidazolidinyl)-æethylester, - (IR,cis )-2,2-dimethy1-3-((2)-2-isopropyloxycarbonyletheny1)--cyclopropancarboxylsyre-l-(R)-3-phenoxyphenylethylester, - (IR,cis)-2,2-dimethy1-3-((2)-2-isopropoxycarbonylethenyl)--cyclopropancarboxylsyre-l-(3-propargyl-2,5-dioxoimidazoli- 10 dinyl)-methylester og - (IR,trans)-2,2-dimethy1-3-((Z)-2-isopropoxycarbonylethenyl)--cyclopropancarboxylsyre-l-(R)-3-phenoxyphenylethylester.4-Cyclopropane carboxylic acid 1- (3-propargyl-2,5-dioxoimidazolidinyl) methyl ester, - (IR, cis) -2,2-dimethyl-3- ((2) -2-cyclopropylmethoxycarboxy-1-thenyl ) -cyclopropane carboxylic acid 1- (3-propargyl-2,5-dioxo-imidazolidinyl) ethyl ester, - (IR, cis) -2,2-dimethyl-3- ((2) -2-isopropyloxycarbonylethenyl) cyclopropane carboxylic acid -1- (R) -3-phenoxyphenylethyl ester, - (IR, cis) -2,2-dimethyl-3- ((2) -2-isopropoxycarbonylethenyl) cyclopropanecarboxylic acid 1- (3-propargyl-2,5- dioxoimidazolidinyl) methyl ester and - (IR, trans) -2,2-dimethyl-3- ((Z) -2-isopropoxycarbonylethenyl) cyclopropane carboxylic acid 1- (R) -3-phenoxyphenylethyl ester.
Præparaterne -ifølge opfindelsen fremstilles efter de sædvanlige processer, som benyttes i den agrokemiske I5 industri, i den veterinære industri eller i dyrefoderindustrien.The compositions of the invention are prepared according to the usual processes used in the agrochemical, veterinary or animal feed industries.
I disse præparater til anvendelse i landbrug og husholdning kan den eller de aktive bestanddele eventuelt være tilsat et eller flere andre pesticide stoffer. Disse præpara-20 ter kan foreligge i form af pudder, granulat, suspensioner, emulsioner, opløsninger, aerosolopløsninger, brændbare strimler eller lokkemad eller andre præparater, som normalt benyttes ved denne slags forbindelser.In these preparations for use in agriculture and household, the active ingredient (s) may optionally be added to one or more other pesticides. These compositions may be in the form of powders, granules, suspensions, emulsions, solutions, aerosol solutions, combustible strips or baits or other preparations normally used in such compounds.
Foruden den aktive bestanddel indeholder disse præpa-25 rater normalt et bindemiddel eller bærestof og/eller et ikke--ionisk overfladeaktivt stof, som desuden sikrer en ensartet fordeling af blandingens bestanddele. Det benyttede bindemiddel eller bærestof kan være en væske såsom vand, ethanol, carbonhydrider eller andre organiske opløsningsmidler, en mi-30 neralsk, animalsk eller vegetabilsk olie, et pudder såsom talkum, ler, silicater, kiselgur eller et fast brændbart stof.In addition to the active ingredient, these preparations usually contain a binder or carrier and / or a nonionic surfactant which further ensures a uniform distribution of the constituents of the mixture. The binder or carrier used may be a liquid such as water, ethanol, hydrocarbons or other organic solvents, a mineral, animal or vegetable oil, a powder such as talc, clay, silicates, diatomaceous earth or a solid combustible substance.
De insekticide præparater ifølge opfindelsen indeholder fortrinsvis 0,005$-10$ aktivt materiale efter vægt.The insecticidal compositions of the invention preferably contain 0.005 $ -10 $ active weight by weight.
Ifølge en fordelagtig udførelsesform benyttes præpara-35 terne ifølge opfindelsen i form af røgpræparater til brug i husholdningen.According to an advantageous embodiment, the compositions of the invention are used in the form of smoke preparations for domestic use.
Præparaterne ifølge opfindelsen kan da med fordel for den inaktive dels vedkommende udgøres af en insekticid røgThe compositions according to the invention can then, for the benefit of the inactive part, be constituted by an insecticidal smoke
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5 spiral eller også et fibrøst ubrændbart substrat. I dette sidste tilfælde anbringes røgpræparatet efter inkorporeringen af det aktive stof i et opvarmet apparat såsom et elektrisk myggeudryd delses apparat, 5 I det tilfælde, hvor man benytter en insekticidspi ral, kan den indifferente bærer f.eks. være af pyrethrumkvas eller tabupulver (pulver af blade af Machilus thumbergii), pyrethrumstilpulver, cederbladpulver, savsmuld, f.eks. af fyrretræ, stivelse og kokosskalpulver.5 or a fibrous non-combustible substrate. In this latter case, after the incorporation of the active substance into the heated apparatus such as an electric mosquito extermination apparatus, the smoke preparation is applied. In the case of using an insecticide spray, the inert carrier may e.g. be of pyrethrum or tabu powder (powder of leaves of Machilus thumbergii), pyrethrum style powder, cedar leaf powder, sawdust, e.g. of pine, starch and coconut shell powder.
10 Dosen af aktivt stof er da f.eks. 0,03-1 vægtprocent.The dose of active substance is then e.g. 0.03-1% by weight.
I det tilfælde, hvor man benytter en ubrændbar fibrøs understøtning, kan dosen af aktivt stof da være f.eks. 0,03-95 vægtprocent.In the case where a non-combustible fibrous support is used, the dose of active substance may then be e.g. 0.03-95% by weight.
Præparaterne ifølge opfindelsen til husholdningsbrug 15 kan også fås, idet man fremstiller en forstøvbar olie på basis af aktivt stof, hvilken olie gennemvæder en lampes væge, som derpå antændes.The compositions of the invention for domestic use 15 may also be obtained by producing an active ingredient sprayable oil which soaks up the wall of a lamp which is then ignited.
Koncentrationen af aktiv bestanddel i olien er da fortrinsvis 0,03-95 vægtprocent.The concentration of active ingredient in the oil is then preferably 0.03-95% by weight.
20 De insekticide præparater ifølge opfindelsen kan lige som de acaricide og nematodicide præparater eventuelt være tilsat et eller flere andre pesticide midler. De acaricide og nematodicide præparater kan især foreligge i fora af pudder, granulat, suspensioner, emulsioner eller opløsninger.The insecticidal compositions of the invention, like the acaricidal and nematodicidal preparations, may be optionally added to one or more other pesticidal agents. In particular, the acaricidal and nematodicidal compositions may be present in forums of powders, granules, suspensions, emulsions or solutions.
25 Til acaricid brag benytter man fortrinsvis fugtbare puddere til forstøvning r-å løvet og indeholdende 1-80$, eller væsker til forstøvning, på løvet indeholdende 1-500 g/liter aktiv bestanddel. Man kan ligeledes benytte pudder til pud-30 ring af løvet og indeholdende 0,05-3$ aktiv bestanddel.For acaricidal debris, wettable powders are preferably used for spraying the r-o leaf and containing 1-80 $, or liquids for spraying, on the leaf containing 1-500 g / liter of active ingredient. Powder can also be used for powdering the foliage and containing 0.05-3 $ active ingredient.
Til nematodicid brug benytter man fortrinsvis væsker til behandling af jorden og indeholdende 300-500 g/liter aktiv bestanddel.For nematodic use, liquids are preferably used for treating the soil and containing 300-500 g / liter of active ingredient.
De acaricide og nematodicide præparater ifølge opfin-35 delsen benyttes fortrinsvis i doser på 1-100 g aktiv bestanddel pr, ha.The acaricidal and nematodicidal compositions of the invention are preferably used in doses of 1-100 g of active ingredient per hectare.
Til forøgelse af den biologiske aktivitet af forbindelsen ifølge opfindelsen kan man tilsætte dem klassiske syner-To enhance the biological activity of the compound of the invention, one may add classic synthetic compounds to them.
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6 gistiske midler, der benyttes i sådanne tilfælde, såsom 1-(2,5,8--trioxadodecyl)-2-propyl-4,5-methylendioxybenzen (eller pipe-ronylbutoxid) eller l\T-(2-ethylheptyl)-bicyclo(2,2-l)-5-hepten--2,3-dicarboximid eller piperonyl-bis-2-(2’-n-butoxyethoxy)-5 -ethylacetal (eller tropital).6 gaseous agents used in such cases as 1- (2,5,8-trioxadodecyl) -2-propyl-4,5-methylenedioxybenzene (or piperonylbutoxide) or 1β- (2-ethylheptyl) - bicyclo (2,2-1) -5-heptene - 2,3-dicarboximide or piperonyl-bis-2- (2'-n-butoxyethoxy) -5-ethylacetal (or tropital).
Når det drejer sig om at bekæmpe acarider som parasitter på dyr, inkorporerer man meget ofte forbindelserne ifølge opfindelsen i næringspræparater i forbindelse med et næringsmiddel beregnet til dyr. Den pågældende blanding kan va-10 riere efter dyrearten, den kan indeholde kornprodukter, sukker og gryn, pressekage af soja, jordnødder og solsikkefrø, mel af animalsk oprindelse, f.eks. fiskemel, syntetiske aminosyrer, mineralsalte, vitaminer og antioxidanter.When it comes to fighting acarides as parasites on animals, the compounds of the invention are very often incorporated into nutritional preparations in conjunction with a food intended for animals. The mixture in question may vary according to the species of animal, it may contain cereals, sugar and cereals, soy press, peanuts and sunflower seeds, flour of animal origin, e.g. fish meal, synthetic amino acids, mineral salts, vitamins and antioxidants.
Opfindelsen angår således også de ovennævnte nærings-15 middelpræparater.Thus, the invention also relates to the aforementioned nutrient preparations.
Forbindelserne med formlen I har en udmærket generel tolerance og kan benyttes hos varmblodede dyr til bekæmpelse af navnlig lidelser, som frembringes af mider og skab, samt til bekæmpelse af lus som præventiv eller kurativ foranstalt-20 ning.The compounds of formula I have an excellent general tolerance and can be used in warm-blooded animals to combat, in particular, disorders caused by mites and creatures, and to combat lice as a preventive or curative measure.
Forbindelserne med formlen I ifølge opfindelsen kan indgives ad ydre vej, ved forstøvning, i form af bad eller ved påsmøring.The compounds of formula I according to the invention can be administered by external route, by spraying, in the form of bath or by application.
Forbindelserne med formlen I ifølge opfindelsen kan 25 ligeledes administreres ved påsmøring på rygraden af dyr ved den såkaldte påhældningsmetode. De kan ligeledes indgives ad fordøjelsesvejen eller parenteralt.The compounds of formula I according to the invention may also be administered by application to the backbone of animals by the so-called pouring method. They can also be administered by the digestive route or parenterally.
Det skal ligeledes angives, at produkterne ifølge opfindelsen kan benyttes som biocider og som vækstregulerende 30 stoffer.It should also be stated that the products of the invention can be used as biocides and as growth regulating agents.
Opfindelsen angår ligeledes en fremgangsmåde til fremstilling af forbindelserne med formlen I, og denne fremgangsmåde er ejendommelig ved det i krav 2's kende-^ tegnende del anførte.The invention also relates to a process for the preparation of the compounds of formula I, and this process is characterized by the characterizing part of claim 2.
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Esterificeringsreaktionen kan udføres efter andre fremgangsmåder. Man kan f.eks. omsætte syren med formlen II med alkohol med formlen III i nærværelse af dicyclohexylcarbo-diimid eller diisopropylcarbodiimid.The esterification reaction can be carried out by other methods. One can, for example. reacting the acid of formula II with alcohol of formula III in the presence of dicyclohexylcarbo diimide or diisopropylcarbodiimide.
5 Forbindelserne med formlen II er hidtil ukendte for bindelser, på hvilke der er givet fremstillingsek?empier i den eksperimentelle del nedenfor.The compounds of formula II are novel to compounds for which manufacturing experiments have been given in the experimental section below.
Forbindelserne med formlen II kan fremstilles ved en fremgangsmåde, ved hvilken man omsætter en forbindelse med formlen IVThe compounds of formula II can be prepared by a process by reacting a compound of formula IV
Halv \== co2aic (IV)Half \ == co2aic (IV)
Hal/ \x \ 15 hvor Hal betegner et halogenatom, og alc betegner en alkyl-gruppe med 1-20 carbonatomer, i et første trin med et alkalisk middel, som er i stand til at løsrive halogenatomeme, og et andet trin,Hal represents a halogen atom, and alc represents an alkyl group of 1-20 carbon atoms, in a first step with an alkaline agent capable of detaching the halogen atoms, and a second step,
enten med et middel, som er i stand til at indføre carboxyl-20 gruppen til opnåelse af forbindelsen med formlen Veither with an agent capable of introducing the carboxyl group to obtain the compound of formula V
H09CSC\ / \ \/ \ (V) 25H09CSC \ / \ \ / \ (V) 25
som man underkaster indvirkning af et esterificeringsmiddel til opnåelse af en forbindelse med formlen VIwhich is subjected to the action of an esterifying agent to obtain a compound of formula VI
30 X \ , N30 X \, N
R02C-C^CL / X jC02alc (VI) hvor R har samme betydning som ovenfor, eller med et alkylchlorformiat med formlen V* R-0-C0-01 (V')R02C-C1 CL / X2 CO2alc (VI) wherein R has the same meaning as above, or with an alkyl chloroformate of the formula V * R-O-C0-01 (V ')
hvor R har samme betydning som ovenfor til direkte opnåelse 35 af forbindelsen med formlen VIwherein R has the same meaning as above for directly obtaining the compound of formula VI
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8 R02C-Csg^ c (VI)8 R02C-Csg3c (VI)
5 hvorefter man underkaster forbindelsen med formlen VI indvirkning af et middel til skånsom hydrogenering til opnåelse af forbindelsen med formlen VII5, then subjecting the compound of formula VI to the effect of a gentle hydrogenation agent to obtain the compound of formula VII
10 M' m i (VII) R02C-C=C / \ C02alc10 M 'm in (VII) R02C-C = C / \ CO2alc
hvor gruppen COgR er i Z-stillingen, som man underkaster indvirkning af et middel til sur hydrolyse, som er i stand til selektivt at spalte den forgrenede estergruppe ved carbonato-met i 1-stillingen, til opnåelse af en tilsvarende forbindelse med formlen IIwherein the group COgR is in the Z-position subjected to the action of an acid hydrolysis agent capable of selectively cleaving the branched ester group at the carbon atom at the 1-position to obtain a corresponding compound of formula II
V-^XV- ^ X
/ X/ 8 (II) ro2c/ X / 8 (II) ro2c
En fremgangsmåde til fremstilling af forbindelserne ·"A Method for Preparing the Compounds · "
25 med formlen I kan bestå i, at man underkaster en forbindelse med formlen VIIIFormula I may consist of subjecting a compound of Formula VIII
HjC CHj f f X*/ (7111) 30 ho2c - 0== σ co-a.· hvor A’ er defineret som ovenfor, indvirkning af et esterifi-ceringsmiddel til opnåelse af forbindelsen med formlen I sva-35 rende dertil«HjC CHj f f X * / (7111) 30 ho2c - 0 == σ co-a. · Where A 'is defined as above, the action of an esterifying agent to give the compound of formula I corresponding thereto «
Forbindelsen med formlen VIII fremstilles, idet man underkaster en forbindelse med formlen IXThe compound of formula VIII is prepared by subjecting a compound of formula IX
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9 H-tGL /CH-t 5 C13C-CH2-02C-CE c N>Vn\^^^CQ25 (12)9 H-tGL / CH-t 5 C13C-CH2-02C-CE c N> Vn \ ^^^ CQ25 (12)
indvirkning af en forbindelse med formlen IIIeffect of a compound of formula III
A'-OH (III)A'-OH (III)
10 hvor A* har samme betydning som ovenfor til opnåelse af en forbindelse med formlen X10 where A * has the same meaning as above to give a compound of formula X
H-C \ / CH, O \ / 15 CX)H-C \ / CH, O \ / 15 CX)
Cl5C-CE2-02C-C£C* / wC02 A'Cl5C-CE2-02C-C £ C * / wC02 A '
* I* I
som man underkaster indvirkning af et middel til spaltning af 20 den estergruppe, som bæres af det acetyleniske carbonatom, til opnåelse af en forbindelse med formlen XIsubjecting to the action of an agent for cleavage of the ester group carried by the acetylenic carbon atom to give a compound of formula XI
E3\ /^3 25 / \ CH) eo2c-esc. / \ ^σο2 A' som man underkaster indvirkning af et middel til skånsom hy-30 drogenering til opnåelse af forbindelsen med formlen VIII.E3 \ / ^ 3 25 / \ CH) eo2c-esc. The effect of a gentle hydrogenation agent is obtained to obtain the compound of formula VIII.
I en foretrukket udførelsesform for fremgangsmåden gælder følgende: - Esterificeringen af forbindelsen IX sker, idet man omsætter forbindelsen IX med alkoholen III i nærværelse af dieyclo- 35.- hexylcarbodiimid eller diisopropylcarbodiimid.In a preferred embodiment of the process, the following applies: - The esterification of compound IX occurs by reacting compound IX with the alcohol III in the presence of dieyclo-35-hexylcarbodiimide or diisopropylcarbodiimide.
- Spaltningen af esteren X sker, idet man benytter et metalpulver, f.eks. zinkpulver i surt milieu.The cleavage of the ester X occurs by using a metal powder, e.g. zinc powder in acidic environment.
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10 - Midlet til skånsom hydrogenering er hydrogen i nærværelse af en katalysator som palladium i nærværelse af spor af quinolin.10 - The gentle hydrogenation agent is hydrogen in the presence of a catalyst such as palladium in the presence of traces of quinoline.
Fremgangsmåden ovenfor omfatter en indlysende variant 5 gående ud på, at hydrogenerings- og esterificeringtrinnene byttes om.The above process comprises an obvious variant 5, which involves the exchange of hydrogenation and esterification steps.
En sådan fremgangsmåde består altså i, at man underkaster en forbindelse med formlen XIThus, such a process consists in subjecting a compound of formula XI
10 EXCX . CE^ \/ m H02 C-C=Cv / c02 A' 15 \Z__10 EXCX. CE2 / m H02 C-C = Cv / c02 A '15 \ Z__
hvor A’ er defineret som ovenfor, indvirkning af et esterifi-ceringsmiddel til opnåelse af en forbindelse med formlen IIIwherein A 'is as defined above, the action of an esterifying agent to give a compound of formula III
/0¾ 20 \ / \/ (HI) H02 C-CSC^^/ \^^c02 A' 25 hvor R og A' har samme betydning som ovenfor, som man underkaster indvirkning af et middel til skånsom hydrogenering til opnåelse af forbindelsen med formlen I.Where R and A 'have the same meaning as above subjected to the action of a gentle hydrogenation agent to obtain the compound with formula I.
le foretrukne forbindelser for udførelsen af fremgangsmåden ovenfor er identiske med dem, som er defineret 30 ovenfor for de analoge operationer.The preferred compounds for carrying out the above method are identical to those defined above for the analog operations.
Forbindelsen med formlen IX kan fremstilles, idet man underkaster en syre med formlen XIIIThe compound of formula IX can be prepared by subjecting an acid of formula XIII
E-,C /CEE-, C / CE
3\Y 5 35 /\> (2111) H02 C02 al c3 \ Y 5 35 / \> (2111) H02 C02 al c
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11 hvor alc betegner en alkylgruppe med 1-8 carbonatomer, indvirkning af 2,2,2-trichlorethanol, hvorpå man underkaster den fremkomne ester en sur hydrolyse.11 where alc represents an alkyl group of 1-8 carbon atoms, the action of 2,2,2-trichloroethanol, upon which the resulting ester is subjected to an acidic hydrolysis.
Et eksempel på fremstilling af en forbindelse med 5 formlen-IX er beskrevet nedenfor i den eksperimentelle del.An example of preparing a compound of Formula IX is described below in the experimental part.
De alkoholer med formlen III, der benyttes ved fremgangsmåden ifølge opfindelsen, er generelt kendte forbindelser. Dog er visse af disse alkoholer, nemlig forbindelserne med formlen 10 ch3 °O~'1,011 15 hvor R^og R-^g har samme betydning som ovenfor, hidtil ukendte og fører til estere, som er helt bemærkelsesværdige fra et biologisk synspunkt.The alcohols of formula III used in the process of the invention are generally known compounds. However, some of these alcohols, namely, the compounds of formula 10, CH 3 0 O, 1,011 15 wherein R 1 and R 2 g have the same meaning as above, are novel and lead to esters which are quite remarkable from a biological point of view.
Blandt disse alkoholer kan specielt nævnes 3-phen-oxy—4—fluor—alpha-methylbenzy1alkohol· Disse alkoholer kan 20 fremstilles som angivet nedenfor i den eksperimentelle del ved indvirkning af en organometalforbindelse, f.eks. et methylmagnesiumhalogenid, på aldehyder svarende til de alkoholer, som man vil fremstille.Among these alcohols may be mentioned especially 3-phenoxy-4-fluoro-alpha-methylbenzyl alcohol. These alcohols can be prepared as set forth below in the experimental part by the action of an organometal compound, e.g. a methyl magnesium halide, on aldehydes corresponding to the alcohols to be prepared.
Nedenstående eksempler illustrerer fremgangsmåden 25 ifølge opfindelsen.The following examples illustrate the method 25 of the invention.
30 3530 35
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• 12• 12
Eksempel 1, (IR, cis , £Z)-2,2-dimethyl-5-(5-methoxy-5-oxo-l-propenyl)-oyolo-propancarboxylsyre-(IS)-2-methyl-4-oxo-3-(2-propenyl)-2-cycle penten-l-y les ter.Example 1, (IR, cis, Z) -2,2-Dimethyl-5- (5-methoxy-5-oxo-1-propenyl) -oyolo-propanecarboxylic acid (IS) -2-methyl-4-oxo 3- (2-propenyl) -2-cycle penten-ly ter.
5 Trin A: (lR„ois,ΔΖ)-2,2-dimethy 1-3-(5-methoxy-5-oxo-l-propenyl)--cyclopropancarboxylsyreohlorid,Step A: (1R „o, ΖΖ) -2,2-Dimethyl 1-3- (5-methoxy-5-oxo-1-propenyl) cyclopropane carboxylic acid chloride,
Man indfører ved 0°C 1 ml thionylchlorid i en blanding af 1,8 g (lR,cis,AZ)-2,2-dimethyl-3-(2-methoxy-3-oxo-l-prope-nyl)-cyclopropancarboxylsyre fremstillet som angivet nedenfor 10 i præparation I og 10 ml isopren, Man holder under omrøring i 30 minutter ved 0°C og derefter ved 20°C i 4 timer. Man inddamper til tørhed under formindsket tryk ved 50°C, Der fås en forbindelse, som man umiddelbart benytter i det næste trin.1 ml of thionyl chloride is introduced into a mixture of 1.8 g (1R, cis, AZ) -2,2-dimethyl-3- (2-methoxy-3-oxo-1-propanol) cyclopropane carboxylic acid prepared as set out below 10 in Preparation I and 10 ml of isoprene. Stir for 30 minutes at 0 ° C and then at 20 ° C for 4 hours. Evaporates to dryness under reduced pressure at 50 ° C. A compound is obtained which is used immediately in the next step.
Trin B: (IR« cis,Δζ)-2,2-dimethyl-3-(3-methoxy-5-oxo-l-propenyl)-15 -cyclopropancarboxyls.vre-( IS )-2-methyl-4-oxo-3-( 2-pro- penyl)2-cyclopenten-l-viester.Step B: (IR, cis, Δζ) -2,2-Dimethyl-3- (3-methoxy-5-oxo-1-propenyl) -15-cyclopropanecarboxylic acid (IS) -2-methyl-4-oxo -3- (2-propenyl) 2-cyclopenten-1-viester.
Man blander 761 mg (4S)-hydroxy-3-methyl-2-(2-prope-nyl)-2-cyclopenten-l-on, 5 ml benzen og 0,4 ml pyridin. Man afkøler opløsningen til 10°C og tilsætter 888 g (IR,cis,AZ)-20 -2,2-dimethyl-3-(3-methoxy-3-oxo-l-propenyl)-cyclopropancarb-oxylsyrechlorid i opløsning i S ml benzen. Man holder reaktionsblandingen under omrøring i 16 timer. Man hælder i vand, dekanterer den organiske fase og vasker den med vand. Man tør-' rer, filtrerer og inddamper til tørhed. Der fås 1,9 g af en 25 forbindelse, som man chromatograferer på silioagel under elue-ring med benzen og ethylacetat (95*5)« Der fås således 1,06 g af den forventede forbindelse, <Xjj = +71,5° +2,5° (c = 0,5$» ceci5).761 mg of (4S) -hydroxy-3-methyl-2- (2-propenyl) -2-cyclopenten-1-one, 5 ml of benzene and 0.4 ml of pyridine are mixed. The solution is cooled to 10 ° C and 888 g (IR, cis, AZ) -20 -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclopropanecarboxylic acid chloride are added in solution ml of benzene. The reaction mixture is kept under stirring for 16 hours. You pour into water, decant the organic phase and wash it with water. Dry, filter and evaporate to dryness. 1.9 g of a compound are obtained which are chromatographed on silio gel eluting with benzene and ethyl acetate (95 * 5). Thus 1.06 g of the expected compound is obtained, <Xjj = + 71.5 ° + 2.5 ° (c = 0.5 $ »ceci5).
I.M.R., CDC15, ppm: 30 1,3 og 1,32, hydrogen i methylgrupperne i 2-stillingen, 1,9-2,05, H i l-stillingen i cyciopropan, 3,1-3,3-3,4, H i 3-stillingen i cyciopropan, 6.5 til 6,8, E ved carbonatomet i l-stillingen i ethenyl, 5,8-6,04, H ved carbon i 2-stillingen i ethenyl, 35 3,7,H i methoxygruppen, 5.6 til 5,8, E ved carbonatomet i 4-stillingen i (4S)-3--methyl-l-oxocyclopent-2-en-4-yl,IMR, CDC15, ppm: 1.3 and 1.32, hydrogen in the methyl groups at the 2-position, 1.9-2.05, H at the 1-position in cyciopropane, 3.1-3.3-3.4 , H at the 3-position in cyciopropane, 6.5 to 6.8, E at the carbon atom at the 1-position in ethenyl, 5.8-6.04, H at the carbon at the 2-position in ethenyl, 3.7, H in the methoxy group, 5.6 to 5.8, E at the carbon atom at the 4-position of (4S) -3-methyl-1-oxocyclopent-2-en-4-yl,
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13 2,95 til 3, K ved carbonatomet i 1-stillingen i propenyl, 5,5 til 6,2, E ved carbonatomet i 2-stillingen i propenyl, 4,8 til 5,2, E ved carbonatomet i 3-stillingen i propenyl.13 2.95 to 3. K at the carbon atom at the 1-position in propenyl, 5.5 to 6.2, E at the carbon atom at the 2-position in propenyl, 4.8 to 5.2, E at the carbon atom at the 3-position in propenyl.
5 Eksempel 2« (IH. cis.AZ)-2.2-d imethyl-5-(5-ethoxy-3-oxo-l-propenyl)-cyclo-propancarboxylsyre-(lS )-2-methyl-4-oxo-3-(2-propenyl)-2-cY-clopenten-I-ylater.Example 2 «(1H, cis.AZ) -2,2-dimethyl-5- (5-ethoxy-3-oxo-1-propenyl) -cyclo-propane carboxylic acid (1S) -2-methyl-4-oxo-3 - (2-propenyl) -2-cy-clopenten-I ylater.
Man indfører 1 g i cyclohexylcarbodiimid, 6 mg 4-di-10 methylaminopyridin og 12 ml methylenchlorid i en kolbe indeholdende 1,1 g (lR,cis,AZ)-2,2-dimethyl-3-(3-ethoxy-3-cxo-l--propenyl)-cyclopropancarboxylsyre fremstillet som angivet nedenfor i præparation 2. Man tilsætter derpå 900 mg (4S)-4--hydroxy-3-methyl-2-(2-propenyl)-2-cyclopent-l-on opløst i 15 1 ml methylenchlorid. Man holder reaktionsblandingen under omrøring i 16 timer. Man filtrerer og inddamper filtratet til tørhed under formindsket tryk og får således 2,4 g af en forbindelse, som man renser ved chromatografi på silicagel. Elue-ringsmiddel: n-hexan og isopropylether (6:4). Her fås 1,3 g 20 af den forventede forbindelse, (Xjj = +34° +2° (c = 0,6$, benzen).1 g of cyclohexylcarbodiimide, 6 mg of 4-dimethylaminopyridine and 12 ml of methylene chloride are introduced into a flask containing 1.1 g (1R, cis, AZ) -2,2-dimethyl-3- (3-ethoxy-3-cxo) -1-propenyl) -cyclopropanecarboxylic acid prepared as set forth below in Preparation 2. 900 mg (4S) -4-hydroxy-3-methyl-2- (2-propenyl) -2-cyclopent-1-one is then dissolved. in 1 ml of methylene chloride. The reaction mixture is kept under stirring for 16 hours. The filtrate is filtered and evaporated to dryness under reduced pressure to give 2.4 g of a compound which is purified by chromatography on silica gel. Eluant: n-hexane and isopropyl ether (6: 4). 1.3 g of 20 of the expected compound are obtained, (Xjj = + 34 ° + 2 ° (c = 0.6 $, benzene).
E.M.R., CDCl^ ppm: 1,27, H i methylgruppeme i 2-stillingen, 3,1-3,4, E ved carbonatomet i 3-stillingen i cyclopropan, 6,4 til 6,8, H ved carbonatomet i 1-stillingen i ethenyl, 25 5,8-6, H ved carbonatomet i 2-stillingen i ethenyl, 1,17, 1,28, 1,4 og 4 til 4,4, H i ethoxy, 4,7 til 5,2, E ved carbonatomet i 3-stillingen i propenyl.EMR, CDCl3 ppm: 1.27, H in the methyl groups at the 2-position, 3.1-3.4, E at the carbon atom at the 3-position in cyclopropane, 6.4 to 6.8, H at the carbon atom at 1- the position in ethenyl, 5.8-6, H at the carbon atom at the 2-position in ethenyl, 1.17, 1.28, 1.4 and 4 to 4.4, H in ethoxy, 4.7 to 5.2 , E at the carbon atom at the 3-position of propenyl.
Eksempel 3.Example 3
30 (IR. cis. ΔΖ)- 2.2-dimeth.vl-3-( 3-oxo-3-propoxv-l-propenyl) -cvolo- propancarboxylsyre-(lS)-2-methyl-4-oxo-5-(2-propenyl)-2-c,yclo-penten-l-vlester.(IR. Cis. ΔΖ) - 2,2-Dimethyl-3- (3-oxo-3-propoxy-1-propenyl) -cvolo-propane carboxylic acid (1S) -2-methyl-4-oxo-5- ( 2-propenyl) -2-c yclo-penten-l-yl ester.
Idet man arbejder som i eksempel 2 ud fra 1,5 g (IR,cis, ΔΖ)-2,2-dimethy1-3-(3-oxo-3-propoxy-1-propenyl)-cyclopropan-35 carboxylsyre og 1,1 g (4S)-4-hydroxy-3-æethyl~2-(2-propenyl)--2-cyclopenten-l-on, får man 3,1 g af den forventede forbindelse, som man renser ved chromatografi på silicagel; elue-ringsmiddel: hexan og isopropylether (7:3). Man inddamper tilWorking as in Example 2 from 1.5 g (IR, cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-3-propoxy-1-propenyl) -cyclopropane-carboxylic acid and 1, 1 g (4S) -4-hydroxy-3-ethyl-2- (2-propenyl) -2-cyclopenten-1-one gives 3.1 g of the expected compound which is purified by chromatography on silica gel; eluent: hexane and isopropyl ether (7: 3). You evaporate to
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tørhed og får 1,7 g af den forventede forbindelse, a^, = +39,5 +2,5° (c = 0,5$, benzen).dryness to give 1.7 g of the expected compound, α + = + 39.5 + 2.5 ° (c = 0.5 $, benzene).
E.M.R., CDCl^, ppm: 1,5 og 1,31, H i methyl i 2-stillingen i cyclopropan, 5 3,1 til 3,42, H ved carbonatomet i 3-stillingen i cyclopropan, 6,4 til 6,8, H ved carbonatomet i 1-stillingen i ethenyl, 5,8-6, E ved carbonatomet i 2-stillingen i ethenyl, 4-4,08-4,2, H i propoxy i α-stilling i forhold til GO2, 0,83-0,95-1,06, H i propoxy i γ-stilling i forhold til C02, 10 5,6 til 5,7, H ved carbonatomet i 4-stillingen i (4S)-3- -methyl-2-(2-propenyl)-l-oxocyclopent-2-en-4-yl, 2, H i methyl i 3-stillingen i (4S)-5-methyl-2-(2-propenyl)-^ -1-oxocyclopent-2-en-4-y1, 4,7 til 5,2, H ved carbonatomet i 5-stillingen i propenyl.EMR, CDCl3, ppm: 1.5 and 1.31, H in methyl at the 2-position in cyclopropane, 3.1 to 3.42, H at the carbon atom at the 3-position in cyclopropane, 6.4 to 6, 8, H at the carbon atom at the 1-position in ethenyl, 5.8-6, E at the carbon atom at the 2-position in ethenyl, 4-4.08-4.2, H in the propoxy at the α position relative to GO2, 0.83-0.95-1.06, H in propoxy at γ position relative to CO 2, 5.6 to 5.7, H at the carbon atom at the 4-position in (4S) -3- -methyl-. 2- (2-propenyl) -1-oxocyclopent-2-en-4-yl, 2, H in methyl at the 3-position of (4S) -5-methyl-2- (2-propenyl) -1 oxocyclopent-2-ene-4-yl, 4.7 to 5.2, H at the carbon atom at the 5-position of propenyl.
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Eksempel 4.Example 4
(IR. ois.ΔΖ)-2.2-dimethyl-3-( 5-( l-methylethox.v)-5-ozo-l-prope-nyl)-cyclopropancarboxylsyre-(lS)-2-methyl-4-oxo-3-(2-prope-nyl)-2-c.vclopenten-l-y lester.(IR. Ois.ΔΖ) -2,2-dimethyl-3- (5- (1-methylethoxyl) -5-ozo-1-propenyl) -cyclopropanecarboxylic acid (1S) -2-methyl-4-oxo- 3- (2-propenyl) -2-cyclopenten-ly ester.
20 Trin A: (IR.cis«ΔΖ)-2,2-dimethy 1-5-(3-1-( 1-methylethoxy)-5--oxo-l-propenyl)-cyclopropancarboxylsyrechlorid.Step A: (IR.cis → ΔΖ) -2,2-dimethyl 1-5- (3-1- (1-methylethoxy) -5-oxo-1-propenyl) -cyclopropane carboxylic acid chloride.
Man omrører 4 timer ved stuetemperatur en blanding af 900 mg (lE,cis,AZ)-2,2-dimethyl-5-(3-(l-methylethoxy)-3-oxo--l-propenyl)-cyclopropancarboxylsyre, 9 ml isopren og 1 ml 25 thionylchlorid. Man inddamper til tørhed og får 1,4 g af en forbindelse, som man umiddelbart benytter i det næste trin.A mixture of 900 mg (1E, cis, AZ) -2,2-dimethyl-5- (3- (1-methylethoxy) -3-oxo-1-propenyl) -cyclopropanecarboxylic acid, 9 ml is stirred for 4 hours at room temperature. isoprene and 1 ml of thionyl chloride. Evaporate to dryness and obtain 1.4 g of a compound which is used immediately in the next step.
Trin B: (lE.cis.AZ)-2.2-dimethvl-5-(5-(l-methylethoxy)-5-oxo--l-propenyl)-cyclopropancarboxylsyre-(lS )-2-meth.vl--4-oxo-5-(2-propenyl)-cvolopenten-l-ylester.Step B: (1E.cis.AZ) -2,2-Dimethyl-5- (5- (1-methylethoxy) -5-oxo-1-propenyl) -cyclopropanecarboxylic acid (1S) -2-methyl-4 -oxo-5- (2-propenyl) -cvolopenten-l-yl ester.
30 Man indfører 1,5 ml pyridin i en blanding indeholdende 1,4 g af den i trin A fremstillede forbindelse, 10 ml benzen og 750 mg (4S)-4-hydroxy-5-methyl-2-(2-propenyl)-cyclopent-2--en-l-on. Man holder reaktionsblandingen under omrøring i 3 timer og hælder i en blanding af isvand og . 2 UT saltsyre (100 ml 35 og 20 ml). Man ekstraherer den vandige suspension med ethyl-acetat. Man vasker de organiske faser med vand indtil neutralitet, tørrer, filtrerer og inddamper filtratet til tørhed un-1.5 ml of pyridine are introduced into a mixture containing 1.4 g of the compound prepared in step A, 10 ml of benzene and 750 mg (4S) -4-hydroxy-5-methyl-2- (2-propenyl) - cyclopent-2 - en-l-one. The reaction mixture is kept under stirring for 3 hours and poured into a mixture of ice water and. 2 UT hydrochloric acid (100 ml 35 and 20 ml). The aqueous suspension is extracted with ethyl acetate. The organic phases are washed with water until neutrality, dried, filtered and evaporated to dryness.
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15 der formindsket tryk. Der fås 2,3 g af en forbindelse, som man chroæatograferer på silicagel; elueringsmiddel: cyclohexan og ethylacetat (8:2), Der fås således 486 mg af den forventede forbindelse, - +26° +2° (c = 0,5$, benzen), 5 U.M.R,,' CDCl^, ppm: 1,28 og 1,32, Hi methylgrupperne i 2-stillingen i cyclo-propan, 1,88-2, H ved carbonatomet i 1-stillingen i cyclopropan, 3,11 til 3,4, H ved carbonatomet i 3-stillingen i cyclopropan, 1° 6,4 til 6,8, H ved carbonatomet i 1-stillingen i ethenyl, 5,8-6, H ved carbonatomet i 2-stillingen i ethenyl, 5, H ved carbonatomet i isopropyl i α-stilling i forhold til C=0, 1,3, H ved carbonatomerne i isopropyl i β-stillingen i for-15 hold til CO, 4,8 til 5,2, H ved carbonatomet i 3-stillingen i propenyl, 5,7, H ved carbonatomet i 4-stillingen i (4S)-3-methyl-2--(2-propenyl )-l-oxocyclopent-2-en-4-yl, 2, H ved carbonatomet i 3-stillingen i (4S)-3-methy1-2-(2-20 -propenyl)-l-oxocyclopent-2-en-4-yl.15 which reduced pressure. 2.3 g of a compound are obtained which are chromatographed on silica gel; eluant: cyclohexane and ethyl acetate (8: 2), thus obtaining 486 mg of the expected compound, - + 26 ° + 2 ° (c = 0.5 $, benzene), 5 UMR ,, CDCl3, ppm: 1 , 28 and 1.32, the Hi methyl groups at the 2-position in cyclopropane, 1.88-2, H at the carbon atom at the 1-position in cyclopropane, 3.11 to 3.4, H at the carbon atom at the 3-position in cyclopropane, 1 ° 6.4 to 6.8, H at the carbon atom at the 1-position in ethenyl, 5.8-6, H at the carbon atom at the 2-position in ethenyl, 5, H at the carbon atom in isopropyl at the α-position in ratio of C = 0, 1.3, H at the carbon atoms of isopropyl at the β-position relative to CO, 4.8 to 5.2, H at the carbon atom at the 3-position at propenyl, 5.7, H at the carbon atom at the 4-position at (4S) -3-methyl-2- (2-propenyl) -1-oxocyclopent-2-en-4-yl, 2, H at the carbon atom at the 3-position at (4S) - 3-methyl-2- (2-20-propenyl) -1-oxocyclopent-2-en-4-yl.
Eksempel 5, (IR, cis.A 1 )-2,2-dimeth.vl-3-( 3-me thoxv-3-oxo-l-propenyl )-cyclo-propancarboxylsyre-( IS )-cyan-( 6-phenoxy-2 -pyrid inyl) -me thyl-25 ester.Example 5, (IR, cis.A1) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane carboxylic acid (1S) -cyan- (6- phenoxy-2-pyridinylmethyl methyl ester.
Man indfører 4,96 g (IR,cis,AZ)-2,2-dimethy1-3-(3-methoxy-3-oxo-l-propenyl)-cyclopropancarboxylsyre i 75 ml methy-lenchlorid. Man tilsætter derpå 2 ml pyridin samt 5,2 g dicy-clohexylcarbodiimid.4.96 g of (IR, cis, AZ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid are introduced into 75 ml of methylene chloride. 2 ml of pyridine and 5.2 g of dicyclohexylcarbodiimide are then added.
30 Man omrører nogle minutter og indfører 5,9 g (RS)-a- -hydroxy-6-phenoxy-2-pyridinacetonitril og derpå 0,1 g 4-di-methylaminopyridin. Man holder reaktionsblandingen 1 time under omrøring og filtrerer derefter. Man inddamper filtratet under formindsket tryk. Man chromatograferer resten på en søj-35 le og benytter som elueringsmiddel cyclohexan og ethylacetat (85:15). På denne måde fås 7,7 g af den forventede forbindelse, Ojj = 59° +2,5° (c = 0,5$>, CHOlj).Stir for a few minutes and introduce 5.9 g of (RS) -α-hydroxy-6-phenoxy-2-pyridinacetonitrile and then 0.1 g of 4-dimethylaminopyridine. The reaction mixture is kept under stirring for 1 hour and then filtered. The filtrate is evaporated under reduced pressure. Chromatograph the residue on a column and use as the eluent cyclohexane and ethyl acetate (85:15). In this way 7.7 g of the expected compound is obtained, Ojj = 59 ° + 2.5 ° (c = 0.5 $>, CHOlj).
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16 Ν,Μ,Ε., CDCl^, ppm: 6.3 H, som bæres af det carbonatom, som bærer C$-gruppen, 1*22 - 1,27 og 1,3 H i methylgruppeme i 2-stillingen i cyclopropan, 5 3,17 til 3,5 H v. carbonatomet i 3-stillingen i cyclopropan, 3.7 H i methox.vgruppen, 5.8 til 6,0 ethylenisk H i α-stilling i forhold til carboxyl-gruppen, 6.3 til 6,6 ethylenisk H i β-stilling i forhold til carboxyl-10 gruppen, 6,9-7 H, som bæres af carbonatomerne i 3- og 5-stillingen i pyridin, 7.7- 7,8-7,9 H, som bæres af carbonatomet i 4-stillingen i pyridin.16 Ν, Μ, Ε., CDCl ^, ppm: 6.3 H carried by the carbon atom bearing the C $ group, 1 * 22 - 1.27 and 1.3 H in the methyl groups at the 2-position in cyclopropane, 3.17 to 3.5 H v. The carbon atom at the 3-position in cyclopropane, 3.7 H in the methoxv group, 5.8 to 6.0 ethylenic H at the α position relative to the carboxyl group, 6.3 to 6.6 ethylenically H at the β position relative to the carboxyl group, 6.9-7 H carried by the carbon atoms in the 3- and 5-position of pyridine, 7.7-7.8-7.9 H carried by the carbon atom of The 4-position in pyridine.
1515
Eksempel 6.Example 6
(IR. cis. ΔΖ )-2.2-d imethyl-3-(5-methoxy-5-oxo-l-propenyl )-oyolo-propancarbox.yls.yre-( 1.3 <4«5.6«7-hexahydro-l,3-dioxo-2H-iso-indol-2-yl)-meth.vlester.(IR. Cis. ΔΖ) -2,2-dimethyl-3- (5-methoxy-5-oxo-1-propenyl) -oyolo-propanecarboxylic acid (1.3 <4> 5.6 «7-hexahydro-1, 3-dioxo-2H-iso indol-2-yl) -meth.vlester.
20 Idet man arbejder som i eksempel 1, trin B, ud fra 1,5 g (lR,cis,AZ)-2,2-dimethyl-3-(methoxycarbonylethenyl)-cyclo-propancarboxylsyrechlorid og 1,4 g 1,3,4,5,6,7-hexahydro-2--hydroxymethyl-lH-isoindol-l,3-(2H)-dion, får man 3 g af en forbindelse, som man chromatograferer på silicagel under elue-25 ring med cyclohexan og ethylacetat (8:2). Man inddamper til tørhed og får 1,86 g af den forventede forbindelse.Working as in Example 1, Step B, from 1.5 g (1R, cis, AZ) -2,2-dimethyl-3- (methoxycarbonylethenyl) cyclopropane carboxylic acid chloride and 1.4 g 1.3, 4,5,6,7-hexahydro-2-hydroxymethyl-1H-isoindole-1,3 (2H) -dione gives 3 g of a compound which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (8: 2). Evaporate to dryness to give 1.86 g of the expected compound.
I.M.R., CDCl^, ppm: 1,27 og 1,3 H i methylgruppeme i 2-stillingen i cyclopropan, 1,78-1,93 H, som bæres af carbonatomet i 1-stillingen i cyclo-30 propan, 3,06-3,53 H, som bæres af carbonatomet i 3-stillingen i cyclopropan, 5.8- 6 ) H, som bæres af carbonatomet i 2-stillin- 6.4 til 6,8 ) gen i ethenylgruppen, 35 3,7 H i methylgruppen i methoxygruppen, 1,6 til 2 H v. 4-, 5-, 6- og 7-carbonatomerne i indol, 5.5 H i methylengruppen i α-stilling i forhold til CO2 forbundet med carbonatomet i 1-stillingen i cyclopropan.IMR, CDCl3, ppm: 1.27 and 1.3 H in the methyl groups at the 2-position in cyclopropane, 1.78-1.93 H carried by the carbon atom at the 1-position in cyclopropane, 3.06 -3.53 H carried by the carbon atom at the 3-position in cyclopropane, 5.8-6) H carried by the carbon atom at 2-still-6.4 to 6.8) gene in the ethenyl group, 3.7 H in the methyl group in the methoxy group, 1.6 to 2 H v. 4-, 5-, 6- and 7-carbon atoms in indole, 5.5 H in the methylene group at the α-position relative to CO2 associated with the carbon atom at the 1-position in cyclopropane.
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Eksempel 7.Example 7
(IR.ciBtåZ^tg-dimethyl-S-tø-methoxy^-oxo-l-propenylJ-cyolo- propancarbox.vlsyre-(5-(phenylmethyl)-3-furanyl)-methylester.(IR, C 1-6 Z 2 tg-dimethyl-5-thymethoxy) -oxo-1-propenyl] -cyclopropanecarboxylic acid (5- (phenylmethyl) -3-furanyl) methyl ester.
Idet man arbejder som i eksempel 1 ud fra 3,22 g (IR, 5 cis,ΔΖ)-2,2-dimethyl-3-(3-methoxy-3-oxo-l-propenyl)-cyclopro-pancarboxylsyrechlorid og 2,8 g 5-(phenylmethyl)-3-furanyl-methanol, får man 6,3 g af en forbindelse, som man chromato-graferer på silicagel under eluering med cyclohexan og ethyl-acetat (8:2). Der fås således 2,33 g af den forventede forbin-10 delse, a-p = +48° +1,5° (c = 0,1%, CHC13).Working as in Example 1 from 3.22 g (IR, 5 cis, ΔΖ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane carboxylic acid chloride and 2, 8 g of 5- (phenylmethyl) -3-furanyl-methanol give 6.3 g of a compound which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (8: 2). Thus, 2.33 g of the expected compound is obtained, a-p = + 48 ° + 1.5 ° (c = 0.1%, CHCl 3).
JST.M.R., CDC13, ppm: 1,26-1,28 H i methylgrupperne i 2-stillingen i cyclopropan, 1,86-2,02 H r,carbonatomet i 1-stillingen i cyclopropan 3,0 til 3,3 H ved carbonatomet i 3-stillingen i cyclopropan, 15 6,4 til 6,8 H ved carbonatomet i 1-stillingen i ethenyl, 5,8-5,9 H ved carbonatomet i 2-stillingen i ethenyl, 3,7 H i methoxygruppen, 4,9 H i CHg-gruppen i α-stilling i forhold til CO, som er forbundet med carbonatomet i 1-stillingen i cyclopropan-20 gruppen, 7,3 H ved carbonatomet i 2-stillingen i furanylgruppen, 6 H ved carbonatomet i 4-stillingen i furanylgruppen, 7,2 aromatiske hydrogenatomer.JST.MR, CDCl3, ppm: 1.26-1.28 H in the methyl groups at the 2-position in cyclopropane, 1.86-2.02 H r, the carbon atom at the 1-position in cyclopropane 3.0 to 3.3 H at the carbon atom at the 3-position in cyclopropane, 6.4 to 6.8 H at the carbon atom at the 1-position in ethenyl, 5.8-5.9 H at the carbon atom at the 2-position in ethenyl, 3.7 H in the methoxy group 4.9 H in the CH 2 group at α position relative to CO, which is linked to the carbon atom at the 1 position of the cyclopropane group, 7.3 H at the carbon atom at the 2 position of the furanyl group, 6 H at the carbon atom at the 4-position in the furanyl group, 7.2 aromatic hydrogen atoms.
25 Eksempel 8.Example 8.
(IR. cis. ΔΖ) -2.2-d imethyl-3- (3 -propox.y-3-oxo-l-propenyl) -c.yclo -propancarboxyls.vre- (1- (2-propeny 1) -2.4 -d ioxoimid azolid in-3 -y 1) --methylester.(IR. Cis. ΔΖ) -2,2-dimethyl-3- (3-propoxyl-3-oxo-1-propenyl) -cyclo-propanecarboxylic acid (1- (2-propenyl) -2.4) -dioxoimide azolidine-3-yl) methyl ester.
Man blander 1,2 g (lR,cis,åZ)-2,2-dimethyl-3-(3-prop-30 oxy-3-oxo-l-propenyl)-cyclopropancarboxylsyre, 20 ml methylen-chlorid og 100 ml 4-dimethylaminopyridin. I den således fremkomne opløsning indfører man derpå 1 g dicyclohexylcarbodiimid. Man indfører under omrøring 900 mg 3-hydroxymethyl-l-(2-propy-nyl)-2,4-imidazolidindion.1.2 g (1R, cis, ÅZ) -2,2-dimethyl-3- (3-prop-oxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid, 20 ml of methylene chloride and 100 ml of 4 -dimethylaminopyridine. 1 g of dicyclohexylcarbodiimide is then introduced into the solution thus obtained. 900 mg of 3-hydroxymethyl-1- (2-propynyl) -2,4-imidazolidinedione are added with stirring.
35 Man omrører i 16 timet ved 20°C og filtrerer. Man va sker filtratet med Hi saltsyre og derpå oed vand til neutralitet, tørrer og inddamper til tørhed under formindsket tryk.35 Stir for 16 hours at 20 ° C and filter. The filtrate was treated with Hi hydrochloric acid and then steamed to neutrality, dried and evaporated to dryness under reduced pressure.
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Der fås en olie, som man chromatograferer på silicagel under eluering med "benzen og ethylacetat (8:2). Der fås 1,2 g af den forventede forbindelse, ccjj = +2° +1° (c = 0,5$, benzen).An oil is obtained which is chromatographed on silica gel eluting with benzene and ethyl acetate (8: 2). 1.2 g of the expected compound is obtained, ccjj = + 2 ° + 1 ° (c = 0.5 $, benzene).
E.M.R,, CDOlj, ppm: 5 1,25 og 1,28 H i methylgrupperne i 2-stillingen, 1,83-1,97 E ved carbonatomet i 1-stillingen i cyclopropan, 3,0 til 3,4 Ξ ved carbonatomet i 3-stillingen i cyclopropan, 6,4 til 6,7 H ved carbonatomet i 1-stillingen i etbenyl, 5,6-5,8 E ved carbonatomet i 2-stillingen i ethenvl, 10 4-4,1-4,2 Ξ i propoxy i α-stilling i forhold til C=0, 0,83-0,95-1,07 H i propoxy i a-stilling i forhold til C=0, 2,33-2,37-2,41 H ved carbonatomet i 3-stillingen i propynyi, 4 H ved carbonatomet i 3-stillingen i 2,5-dioxoimidazolidinyl, 4,2-4,3 E i methylengruppen i α-stilling i forhold til den 15 tredobbelte binding.EMR, CDOlj, ppm: 5 1.25 and 1.28 H in the methyl groups at the 2-position, 1.83-1.97 E at the carbon atom at the 1-position in cyclopropane, 3.0 to 3.4 Ξ at the carbon atom at the 3-position in cyclopropane, 6.4 to 6.7 H at the carbon atom at the 1-position in etbenyl, 5.6-5.8 E at the carbon atom at the 2-position in ethylene, 10-4.1-4, 2 Ξ in propoxy at α position relative to C = 0, 0.83-0.95-1.07 H in propoxy at α position relative to C = 0, 2.33-2.37-2, 41 H at the carbon atom at the 3-position in propynyl, 4 H at the carbon atom at the 3-position in 2,5-dioxoimidazolidinyl, 4.2-4.3 E in the methylene group at the α-position relative to the triple bond.
Eksempel 9.Example 9
(1 E« cis, ΔΖ) -2.2-aime thvl-5-(3-oxo-3-methoxy-l-propen.vl )--cyclopropan-l-carboxylsyre-m-phenoxybenzylester.(1 E, cis, ΔΖ) -2,2-dimethyl-5- (3-oxo-3-methoxy-1-propenyl) cyclopropane-1-carboxylic acid m-phenoxybenzyl ester.
20 I 20 ml methylenchlorid indfører man 2 g (ΐΕ,οϊε,ΔΖ)- -2,2-d ime thyl-3-(3-oxo-3-methoxy-l-propeny1)-cyclopropan-1--carboxylsyre, 0,9 ml pyridin og 2,5 g dicyclohexylcarbodi-imid. Man omrører 10 minutter, tilsætter 2,4 g m-phenoxyben-zylalkohol og omrører 1 time 30 minutter, tilsætter 40 mg di-25 methylaminopyridin, omrører 2 timer 30 minutter, eliminerer det dannede uopløselige materiale ved filtrering, inddamper filtratet til tørhed under formindsket tryk, chromatograferer resten på silicagel under eluering med en blanding af cyclo-hexan og ethylacetat (9:1) og får 3 g (lR,cis,AZ)-2,2-dime-30 thyl-3-(3-oxo-3-methoxy-l-propenyl)-cyclopropan-1-carboxylsyre--m-phenoxybenzylester, a^ + 48° +1,2° (c = 1$, chloroform).20 g of methylene chloride are charged with 2 g of (ΐΕ, οϊε, Δ -) -2,2-dimethyl-3- (3-oxo-3-methoxy-1-propenyl) -cyclopropane-1-carboxylic acid, , 9 ml of pyridine and 2.5 g of dicyclohexylcarbodiimide. Stir for 10 minutes, add 2.4 g of m-phenoxybenzyl alcohol and stir for 1 hour 30 minutes, add 40 mg of dimethylaminopyridine, stir for 2 hours 30 minutes, eliminate the insoluble material formed by filtration, evaporate the filtrate to dryness under reduced pressure. pressure, chromatograph the residue on silica gel eluting with a mixture of cyclohexane and ethyl acetate (9: 1) to give 3 g (1R, cis, AZ) -2,2-dimethyl-3- (3-oxo- 3-methoxy-1-propenyl) -cyclopropane-1-carboxylic acid - m-phenoxybenzyl ester, α + + 48 ° + 1.2 ° (c = 1 $, chloroform).
Analyse: C23H24°5 = 380,444 beregnet: C$ 72,61 Ξ$ 6,36 fundet: 72,7 6,4 35 I analogi med eksempel 9 kan man ud fra passende syrer og alkoholer fremstille følgende forbindelser:Analysis: C23H24 ° 5 = 380.444 calculated: C $ 72.61 Ξ $ 6.36 found: 72.7 6.4 35 In analogy to Example 9, the following compounds can be prepared from the appropriate acids and alcohols:
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Eksempel 10.Example 10.
(IR« cis.AZ )-2. 2-dime thy 1-3-( 3-methoxy-3-oxo-l-propenyl )-cyclo-propan-1-carboxylsyre -g- (ES) -cy an-( 3 - (4 -bromphenoxy) -phenyl) --methylester, 5 Analyse: 02/1^22^^^5 ~ 484»342 beregnet: C$ 59,51 H$ 4,58 Br$ 16,50 11$ 2,89 fundet: 59,7 4,6 16,2 2,8 CDCl^: - toppe fra 1,26 til 1,34 ppm, som tillægges hydrogenatornerne 10 i tvillingmethylgrupperne, - toppe ved 1,97-2,06 og fra 3,22 til 3,48 ppm, som tilskrives bydrogenatomerne i 1- og 3-stillingen i cyclopropyl, - toppe ved 3,7-3,73 ppm, som tilskrives hydrogenatomerne i C02-CH3, 15 - toppe ved 5,85-5,98 og 5,9-6,03 ppm, som tilskrives de ethyleniske hydrogenatomer (estersiden), - top ved 6,33 ppm, som tilskrives hydrogenatomet i -CH-CN, - toppe fra 6,43 til 6,67 ppm, som tilskrives de ethyleniske hydrogenatomer (cyclopropylsiden), 20 - toppe fra 6,85 til 7,52 ppm, som tilskrives hydrogenato merne i bromphenyl, - toppe fra 6,94 til 7,55 ppm, som tilskrives hydrogenatomerne i den anden aromatiske ring.(IR) cis.AZ) -2. 2-dimethyl-1-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid-g- (ES) -cyan- (3- (4-bromophenoxy) -phenyl) - Methyl ester, 5 Analysis: 02/1 ^ 22 ^^^ 5 ~ 484 »342 Calcd: C $ 59.51 H $ 4.58 Br $ 16.50 11 $ 2.89 Found: 59.7 4.6 16.2 2.8 CDCl 3: - peaks from 1.26 to 1.34 ppm, which are added to the hydrogen atoms 10 in the twin methyl groups, - peaks at 1.97-2.06 and from 3.22 to 3.48 ppm, which are attributed to the urban drug atoms at the 1 and 3 positions in cyclopropyl, - peaks at 3.7-3.73 ppm, which are attributed to the hydrogen atoms in CO 2 -CH3, 15 peaks at 5.85-5.98 and 5.9-6, 03 ppm attributed to the ethylenic hydrogen atoms (ester side), - peak at 6.33 ppm attributed to the hydrogen atom in -CH-CN, - peaks of 6.43 to 6.67 ppm attributed to the ethylenic hydrogen atoms (cyclopropyl side), 20 - peaks from 6.85 to 7.52 ppm attributed to the hydrogen atoms in bromophenyl, - peaks from 6.94 to 7.55 ppm attributed to the hydrogen atoms in the second aromatic ring.
25 Eksempel 11.Example 11.
(IB. cis.AZ)-2.2-d imethy1-3-(3-me thoxy-3-oxo-l-propenyl)-cyclo-propan-l-carboxylsyre~4-oxo-4-(H)-pyran-3-ylester. smp. 106°C, ocD = +153° ++2,5° (c *= 0,8$, benzen) 30 Eksempel 12.(IB. Cis.AZ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid ~ 4-oxo-4- (H) -pyranic acid 3-yl ester. mp. 106 ° C, ocD = + 153 ° ++ 2.5 ° (c * = 0.8 $, benzene) Example 12.
(IR.cis,ΔΖ)-2.2-d imethyl-3-(3-is opropoxy-3-oxo-l-propenyl)--cyclopropan-l-carboxylsyre-l-(R)-( 3-phenoxyphenyl)-eth.vlester. ocp = +140° +2,5° (c = 1$, benzen) 35 Eksempel 13.(IR.cis, ΔΖ) -2,2-dimethyl-3- (3-isopropoxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid 1- (R) - (3-phenoxyphenyl) -eth .vlester. ocp = + 140 ° + 2.5 ° (c = 1 $, benzene) Example 13.
(lR.cis.AZ)-2.2-dlmethyl-3-(5-ethoxy-5-oxo-l-propenyl)-cyclo-propan-l-carboxylsyre -1- (R)-(3-phenoxvphen.vl) -e th.vles ter.(1R.cis.AZ) -2,2-dimethyl-3- (5-ethoxy-5-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid -1- (R) - (3-phenoxyphenyl) - e th.vles ter.
Op = +145° ±2,5° (c = 1$, benzen)At = + 145 ° ± 2.5 ° (c = 1 $, benzene)
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Eksempel 14.Example 14.
(IR, cis, Δ2 )-2,2-d imethyl-( 3-( 5-methoxy-5-oxo-l-propen.yl)-c.yelo-propan-l-carboxylsyre-l-(R)-(3-phenoxyphenyl)-ethylester, ajj = +130,5° +2,5° (c = 1$, chloroform) 5(IR, cis, Δ2) -2,2-dimethyl- (3- (5-methoxy-5-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid 1- (R) - (3-phenoxyphenyl) ethyl ester, ajj = + 130.5 ° + 2.5 ° (c = 1 $, chloroform)
Eksempel 15.Example 15
(1 R.cis.AZ)-2.2-0imeth.yl-5-(5-methoxy-3-oxo-l-propenyl)-cyolo-propan-l-carboxylsyre-(RS)-a-cyan-(5-benzoylphenyl)-methylester. aD = +43° i·*·0 (° = toluen) 10(1R.cis.AZ) -2.2-dimethyl-5- (5-methoxy-3-oxo-1-propenyl) -cyolo-propane-1-carboxylic acid (RS) -α-cyano- (5- benzoylphenyl) methyl ester. aD = + 43 ° i · * · 0 (° = toluene) 10
Eksempel 16, (IR,cis,Δ Z)-2,2-dime thy1-3-(3-me thoxy-3-oxo-1-propeny1)-cyolo-propan-1-carboxylsyre-(5-benzoylphenyl)-methylester, aE = +5^° ±1,5° ( c = 1$, chloroform) 15Example 16, (IR, cis, Δ Z) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyolo-propane-1-carboxylic acid (5-benzoylphenyl) methyl ester, αE = + 5 ° ± 1.5 ° (c = 1 $, chloroform) 15
Eksempel 17, (IR,cis,ΔΖ)-2,2-åimethvl-3-ί 5-methoxy-3-oxo-l-propenyl)-cyclo-propan-l-carh oxyIs yre-(2,5.4,5,6-pentafluorpheny1)-methylester.Example 17, (IR, cis, ΔΖ) -2,2-dimethyl-3-yl-5-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid (2,5,4,5, 6-pentafluorpheny1) methyl ester.
«jj = +29,5° +2° (c = 0,8fo, chloroform) 20+ = 29.5 ° + 2 ° (c = 0.8 °, chloroform) 20
Eksempel 18.Example 18.
(IR,cis,AZ)-2,2-dimethyl-3~(3-methoxy-3-oxo-l-propenyl)-cyclo-propan-l-carboxylsyre-(RS)-cyan-(2,5,4«5,6 -pentafluorphenyl)--methylester, 25 Analyse: = 403,31 beregnet: C$ 53,61 H# 3,50 1$ 3,47 Ή 23,55 fundet: 53,9 3,5 3,4 23,7(IR, cis, Z) -2,2-dimethyl-3- (3-methoxy-3-oxo-l-propenyl) -cyclo-propane-l-carboxylic acid (RS) -cyano (2,5,4 5,6-Pentafluorophenyl) methyl ester, Analysis: = 403.31 calculated: C $ 53.61 H # 3.50 1 $ 3.47 Ή 23.55 Found: 53.9 3.5 3.4 23.7
Eksempel 19.Example 19.
30 (IR, ois, Δ2 )-2,2-dime thyl-5-(5-oxo-3-n-propox.y-l-propenyl )-cyclo-propan-l-carboxylsyre-(RS )-c.yan-2-(6-phenoxypyridyl)-me thy lester, otjj = +55° +2,5° (c = 0,5f°t chloroform)(IR, ois, Δ2) -2,2-dimethyl-5- (5-oxo-3-n-propoxyl-propenyl) -cyclo-propane-1-carboxylic acid (RS) -cyanamide 2- (6-Phenoxypyridyl) -me thyl ester, ot
Eksempel 20.Example 20
35 (IR,cis,ΔΖ)-2,2-dimethyl-3-(3-propoxy-3-oxo-l-propenyl)-ovolo- propan-1-carboxylsyre -llM[5-Phenoxyphenyl)-ethvlester.(IR, cis, ΔΖ) -2,2-dimethyl-3- (3-propoxy-3-oxo-1-propenyl) -ovolo-propane-1-carboxylic acid-11M [5-phenoxyphenyl) ethyl ester.
Ojj = +123° +2° (c = 0,9/3, chloroform)Ojj = + 123 ° + 2 ° (c = 0.9 / 3, chloroform)
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Eksempel 21, (lH,cis<AZ)-2,2'-dimethyl--3-(3-methoxy-3-oxo-l-propenyl)-cyolo- propan-l-carboxylsyre-l-(R)-5-phenox.vphenyl)-2-propyn-l-yleEter.Example 21, (1H, cis <AZ) -2,2'-Dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid 1- (R) -5 -phenox.vphenyl) -2-propyn-l-yleEter.
= +55,5° +1,5° (c = Vfo, chloroform) 5= + 55.5 ° + 1.5 ° (c = Vfo, chloroform) 5
Eksempel 22, (lR.cis«AZ)-2.2-aimeth.vl-3-(3-isopropoxy-5-oxo-l-propenyl)-cyclo-propan-l->carboxylsyre-l-(R)-(3-phenoxyphen.yl)-2-propyn-l-y lester, smp. 66UC.Example 22, (1R.cis + AZ) -2,2-dimethyl-3- (3-isopropoxy-5-oxo-1-propenyl) -cyclo-propane-1- (carboxylic acid) 1- (R) - (3 -phenoxyphenyl) -2-propynyl ester, m.p. 66UC.
10 = +47° +i° ( c * 1,256, chloroform)= + 47 ° + i ° (c * 1.256, chloroform)
Eksempel 23.Example 23
(lR«cis.AZ)-2,2-dimethyl-3-(3-P-propoxy-3~oxo~l~propenyl)~oyclo-propan~l-»ca.rboxyls.yre~lR~(,3~pheGoxyphenyl)-2~propyn~l-yles ter.(R 'cis.AZ) -2,2-dimethyl-3- (3-p-propoxy-3 ~ oxo ~ l ~ propenyl) ~ oyclo-propane ~ L-' ca.rboxyls.yre ~ R ~ (, 3 ~ pheGoxyphenyl) -2 ~ propyn ~ l-yles ter.
15 = +48° +2° (c = 156, chloroform).= + 48 ° + 2 ° (c = 156, chloroform).
Eksempel 24.Example 24.
(lR,cis.AZ)-2.2-dimethyl-3-(3-methoxy-3-oxo-l-propenyl)-cyclo~ propan »l-carbox.yls.yre~ (4 -benzoylphenyl )-methy lester.(1R, cis.AZ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid ~ (4-benzoylphenyl) methyl ester.
20 =46° +2° (c = I56, chloroform)20 = 46 ° + 2 ° (c = I56, chloroform)
Eksempel 25.Example 25
(IR, cis. AZ )-2.2-dimethvl-3-( 3-oxo-3-tert. -butoxy-l-propenyl) --oy olopropan-l-carboxylsyre-(RS)-cyan-2-( 6-phenox.ypyridyl )-25 -methylester.(IR, cis. AZ) -2,2-Dimethyl-3- (3-oxo-3-tert-butoxy-1-propenyl) -ylopropane-1-carboxylic acid (RS) -cyan-2- (6- phenoxypyridyl) -25 methyl ester.
Ojj = +68° +1,5° (c =156, chloroform)= 68 ° + 1.5 ° (c = 156, chloroform)
Eksempel 26.Example 26
(IR.cis.ΔΖ)-2. 2-dime th vl-5-(3-methoxy~3-oxo-l-propen.yl )-cyclo- , 30 propan-1-carboxylsvre-(RS)-oyan-(4-benzoylphenyl)-methylester. Analyse: G25^23^5^ = 417,466 beregnet: C$ 71,93 H$ 5,85 tø° 3,35 fundet: 71,9 5,8 3,2 35 Eksempel 27.(IR.cis.ΔΖ) -2. 2-dimethyl-5- (3-methoxy-3-oxo-1-propenyl) -cyclo-, propane-1-carboxylic acid (RS) -oyan- (4-benzoylphenyl) methyl ester. Analysis: G25 ^ 23 ^ 5 ^ = 417.446 Calc'd: C $ 71.93 H $ 5.85 t0 3.35 Found: 71.9 5.8 3.2 35 Example 27.
(IR. cis.AZ) -2«2-d ime thvl-3-( 3-oxo-3-tert,-butoxy-1-propenyl)- ~oyclopropan-l-carboxylsyre~(5-prop.yn-2-.yl-2,3--dioxolmidazoli‘- dinyl)~meth.vlester.(IR. Cis.AZ) -2- 2-dimethyl-3- (3-oxo-3-tert-butoxy-1-propenyl) oyclopropane-1-carboxylic acid ~ (5-propynyl-2 -yl-2,3-dioxolmidazoli-dinyl] -methyl ester.
= +^l° +2° (c = 0.556. chloroform).= + 1 ° + 2 ° (c = 0.556. chloroform).
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Eksempel 28« (lR.cis«AZ)-2.2-dimethyl-5-(5-isopropox.y-5-oxo-l-propenyl)--cyclopropan-l-carboxylsyre-(5-propyn-2-yl-2«5 -d ioxoimid azol-idinyl)-methylester. snp. 78°C.Example 28 "(1R.cis" AZ) -2,2-Dimethyl-5- (5-isopropoxy-5-oxo-1-propenyl) cyclopropane-1-carboxylic acid (5-propyn-2-yl-2 (5-Dioxoimide azole-idinyl) methyl ester. SNP. 78 ° C.
5 ajj =+15»5° +1° (c = Ifo, chloroform)Ajj = + 15 »5 ° + 1 ° (c = Ifo, chloroform)
Eksempel 29« (IR« cis«Ag)-2«2-dimethyl-3-( 5-o.vclobutoxy-3-oxo-l-propenyl)--oyclopropan-l-carboxylsyre-( 3-propyn-2-y'i-2«5-d ioxoimidazol-10 idinyl)-methylester.Example 29 "(IR" cis "Ag) -2" 2-Dimethyl-3- (5-oclobutoxy-3-oxo-1-propenyl) oyclopropane-1-carboxylic acid (3-propyn-2-y (2- (5-Dioxoimidazole-idinyl) methyl ester.
α-Q = +18° +1° (c = 1,2$, chloroform)α-Q = + 18 ° + 1 ° (c = 1.2 $, chloroform)
Eksempel 50« (IR« cis«ΔΖ )-2«2-d imethyl-5-(5-isobutoxy-5-oxo-l-propenyl)-15 -cyclopropan-l-carboxylsyre- i 3-propyn-2-yl-2 «5-dioxoimidazol-idinyl)-methylester. α-Q =+20,5° +1,5° (c = 1$, chloroform)Example 50 "(IR" cis "ΔΖ) -2" 2-Dimethyl-5- (5-isobutoxy-5-oxo-1-propenyl) -15-cyclopropane-1-carboxylic acid 3-propyn-2-yl 2- (5-Dioxoimidazole-idinyl) methyl ester. α-Q = + 20.5 ° + 1.5 ° (c = 1 $, chloroform)
Eksempel 51« 20 (lR.ois.AZ)-2.2-dimeth.yl-5-(5-oxo-3-ethoxy-l-propenyl)-oyclo-propan-l-carboxylsyre-(5-propyn-2-yl-2«5-dioxoimidazolidinyl)--methylester.EXAMPLE 51 (20Roisoaz) -2,2-Dimethyl-5- (5-oxo-3-ethoxy-1-propenyl) oyclo-propane-1-carboxylic acid (5-propyn-2-yl) -2 '5-dioxoimidazolidinyl) -, methyl ester.
a-p = +10° +4° (c = 0,2$, chloroform) 25 Eksempel 52.α-β = + 10 ° + 4 ° (c = 0.2 $, chloroform) Example 52.
(lR.cis.AZ)‘-2.2-dimethyl-5-(5-ethoxy-5-oxo-l-propenylcyolopropan- -l-carboxyls.yre-l-(R)-(5-phenoxyphenyl)-2-prop.yn-l-ylester.(1R.cis.AZ) - 2,2-Dimethyl-5- (5-ethoxy-5-oxo-1-propenylcyolopropane-1-carboxylic acid-1- (R) - (5-phenoxyphenyl) -2-prop .yn-l-yl ester.
Ojj = +48,5° +2° (chloroform) 30 Eksempel 35« (IR« cis« ΔΖ )-2.2-dime thyl-3~( 3~oxo-5~isopropoxy--l-propenyl)-o.y-clopropan-1-carboxylsyre-(5-beaz.yl-5-fur.yl )-methylester. ccjj = +44° +2° (c = 0,4$, chloroform) 35 Eksempel 34.Ojj = + 48.5 ° + 2 ° (chloroform) Example 35 "(IR" cis "ΔΖ) -2,2-Dimethyl-3 ~ (3 ~ oxo-5-isopropoxy-1-propenyl) -ylo-clopropane -1-carboxylic acid (5-benzyl-5-furyl) methyl ester. ccjj = + 44 ° + 2 ° (c = 0.4 $, chloroform) Example 34.
(IR« cis«ΔΖ) -2«2-d ime thy 1-3-( 3-oxo-3-is opropox.ypropenyl) -cy clo - propan-l-carboxylsyre-m-phenoxybenzylester.(IR c cis ΔΖ) -2 «-dimethyl-1-3- (3-oxo-3-isopropoxy-propenyl) -cyclo-propane-1-carboxylic acid m-phenoxybenzyl ester.
ctjj = +42° +2° (c = 0,5$, chloroform).ctjj = + 42 ° + 2 ° (c = 0.5 $, chloroform).
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Eksempel 55« &R.ois.ΔΖ)- 2.2-dimethyl-3-(3-οχο-3-Γcvclopropylmethoxy)-pro-penyl)-O.yclopropan-l-carbox.vlsyre-(RS )-cyan-2-(6-phenox.yp.yri-dyl)-methylester.Example 55 (& R.ois.ΔΖ) - 2,2-Dimethyl-3- (3-chloro-3-cyclopropylmethoxy) -propenyl) -ocyclopropane-1-carboxylic acid (RS) -cyan-2- ( 6-phenox.yp.yri-dyl) methyl ester.
5 = +53° +2° (c = 0,5$, chloroform)5 = + 53 ° + 2 ° (c = 0.5 $, chloroform)
Eksempel 56.Example 56
(IR« cis.ΔΖ)-2,2-dlme-fchy1-3-(5-oxo-5-n-propoxypropenyl)-cyclo--propan-l-carboxylsyre-y 5-benzyl-5-furyl)-methylester, 10 α-rj = +41° +2° (c = 0,5$, chloroform)(IR (cis.ΔΖ) -2,2-dimethylchyl-3- (5-oxo-5-n-propoxypropenyl) -cyclopropane-1-carboxylic acid γ-5-benzyl-5-furyl) methyl ester , Α-rj = + 41 ° + 2 ° (c = 0.5 $, chloroform)
Eksempel 57.Example 57.
(ia.cis«AZ)-2,2-aimeth.yl-5-(3-oxo-5-isopropoxypropenyl)-c.yclo-propan-l-carboxylsyre-1.5.4.5«6«7-hexahydro-1.5-dioxo-2H-iso-15 in*3ol-2-yl)-methylester. smp« 94°C.(Ia.cis' AZ) -2,2-aimeth.yl-5- (3-oxo-5-isopropoxypropenyl) -c.yclo-propan-l-carboxylic acid 1.5.4.5 '6' 7-hexahydro-1,5- dioxo-2H-iso-15 * (3ol-2-yl) methyl ester. mp 94 ° C.
Or) - -22,5° +2° (o = o,5$, chloroform).Or) - -22.5 ° + 2 ° (o = o, $ 5, chloroform).
Eksempel 58.Example 58
(ljR.cis.AZ)-2,2~d ime th ,vl -5-(3 -ox o-5 -n -pr opoxy -1 -pro peny 1) -py c lo -20 Propan-l-carboxylsyre-(l.5.4«5«6«7-hexahydro-1.3-dioxo-2H-iso-indol-2-yl)~meth.vlester« smp. 76°C.(ljR.cis.AZ) -2,2 ~ d ime th, yl -5- (3-oxo-5-n-pr opoxy-1-propenyl) py clo-20 Propane-1-carboxylic acid - (1.5.4 "5" 6 "7-Hexahydro-1,3-dioxo-2H-iso-indol-2-yl) -methyl ester" m.p. 76 ° C.
(¾ =-15° (c = 0,15$, carbontetrachlorid^(15 = -15 ° (c = 0.15 $, carbon tetrachloride)
Eksempel 59.Example 59.
25 (IR« cis. ΔΖ )-2.2-d imethyl-5--( 5-oxo-5 '-n-propoxy-l-propepyl)- -cyclopropan-1-carboxylsyre-m-pheaoxybenzylester. oc^ = +40° +2° (c = 0,5$, chloroform)(IR) cis. ΔΖ) -2,2-dimethyl-5- (5-oxo-5'-n-propoxy-1-propepyl) -cyclopropane-1-carboxylic acid m-pheaoxybenzyl ester. = + 40 ° + 2 ° (c = 0.5 $, chloroform)
Eksempel 40.Example 40.
30 (1 R.cis.AZ)-3-(5-oxo-5-cyclopropylmethoxy-l-propenyl)-cyolo-propan-l-carboxylsyre-m-phenoxybenzylester.(1R.cis.AZ) -3- (5-oxo-5-cyclopropylmethoxy-1-propenyl) -cyolo-propane-1-carboxylic acid m-phenoxybenzyl ester.
(¾ = +46,5° +2° (c = 0,6$, chloroform)(¾ = + 46.5 ° + 2 ° (c = 0.6 $, chloroform)
Eksempel 41.Example 41.
35 (lR«cis.AZ)-2.2-dimethyl-5-(5-cyclobutoxy-5-oxo-l-propenyl)--cyclopropan-1-carboxylsyre-1-(R)-(5-phenoxyphenyl)-ethyles te r. (¾ = +125,5° +2° (c = 1$, chloroform)(1R-cis.AZ) -2,2-dimethyl-5- (5-cyclobutoxy-5-oxo-1-propenyl) -cyclopropane-1-carboxylic acid 1- (R) - (5-phenoxyphenyl) ethyl te r. (¾ = + 125.5 ° + 2 ° (c = 1 $, chloroform)
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Eksempel 42.Example 42
(IR« cis ,AZ)-2, 2-dimethyl-3-(3-oxo-5-(cyclopropylmethoxy)-1-pro-penyl) -cyclopropan-l-carboxylsyre-( 1,5«4«5«6,7-hexahyd ro-1,3--dioxo-2H-isoindol-2-yl)-methylester, smp. 102°C, 5 = +6,5° +2° (c = 0,3$, chloroform)(IR, cis, AZ) -2,2-Dimethyl-3- (3-oxo-5- (cyclopropylmethoxy) -1-propenyl) -cyclopropane-1-carboxylic acid (1.5 7-Hexahydro-1,3-dioxo-2H-isoindol-2-yl) methyl ester, m.p. 102 ° C, 5 = + 6.5 ° + 2 ° (c = 0.3 $, chloroform)
Eksempel 45.Example 45
(IR,cis,AZ)-2.2-dimethyl-3-(3-oxo-5-(cyclopropylmethoxy)-l-pro-penyl)-cyclopropan-l-carboxylsyre-(5-benzyl-3-furyl)-methylester. 10 ajj = +42° +2° (c = 0,7$, chloroform)(IR, cis, Z) -2.2-dimethyl-3- (3-oxo-5- (cyclopropylmethoxy) -l-propenyl) -cyclopropane-l-carboxylic acid (5-benzyl-3-furyl) methyl ester. Ajj = + 42 ° + 2 ° (c = 0.7 $, chloroform)
Eksempel 44.Example 44
(IR, cis,ΔΖ)-2,2-dimethyl-3-(3-oxo-3-(cyclopropylmethoxy)-1-pro-penyl)-cyclopropan-l-oarboxylsyre-(S)-2-methyl-4-oxo-3-(2-pro-15 penyl)-2~cyolopentenylester< otjj = +64,5° +2,5° (c = 1$, chloroform)(IR, cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-3- (cyclopropylmethoxy) -1-propenyl) -cyclopropane-1-oreboxylic acid (S) -2-methyl-4 oxo-3- (2-propenyl) -2-cyolopentenyl ester <oj = + 64.5 ° + 2.5 ° (c = 1
Eksempel 45.Example 45
(IR. cis. ΔΖ) -2,2-dlmeth.yl-3-(5~cyclopentyloxy-3-oxo-l-propeny3>-20 cyclopropan-l-carboxylsyre-(3-propyn-2-yl-2,5-dioxoimidazol-idinyl)-methylester, aD = +15,5° +1,5° (c = 1$, chloroform)(IR. Cis. ΔΖ) -2,2-dimethyl-3- (5-cyclopentyloxy-3-oxo-1-propenyl) -20-cyclopropane-1-carboxylic acid (3-propyn-2-yl-2) 5-dioxoimidazole-idinyl) methyl ester, α D = + 15.5 ° + 1.5 ° (c = 1 $, chloroform)
Eksempel 46.Example 46
25 (IR, cis, ΔΖ)-2,2-dimethyl-3-(5-oxo-5-oyolopentyloxy-l-propenyl)--cyclopropan-l-carboxylsyre-(RS)-cyan-2-(6-phenoxy-6-pyriainyl)--methylester.(IR, cis, ΔΖ) -2,2-dimethyl-3- (5-oxo-5-oyolopentyloxy-1-propenyl) cyclopropane-1-carboxylic acid (RS) -cyan-2- (6-phenoxy) -6-pyriainyl) -, methyl ester.
Oj) = +42° +1° (c = 0,9$, benzen) 30 Eksempel 47« (IR,cis,ΔΖ)-2,2-dimethyl-5-(5-methoxy-5-oxo-l-propenyl)-oyclo-propan-l-carboxylsyre-(5-propyn-2-yl-2,5-dioxoimidazolidinyl)--methylester, a-n = ca. +1° (c = 0,5$, benzen)Oj) = + 42 ° + 1 ° (c = 0.9 $, benzene) Example 47 + (IR, cis, ΔΖ) -2,2-dimethyl-5- (5-methoxy-5-oxo-1 propenyl) oyclo-propane-1-carboxylic acid (5-propyn-2-yl-2,5-dioxoimidazolidinyl) methyl ester, an = ca. + 1 ° (c = 0.5 $, benzene)
Xj 99 35Xj 99 35
Eksempel 48, (IR, cis, ΔΖ )-2,2-aime thyl-5-(5-se c, -butoxy-3-oxo-l-propenyl )-cy-clopropan-l-oarboxylsyre-(3-propyn-2-yl-2,5-d ioxoimid azolid iny1)--methylester, n +16,5υ +1° (c = o,S$, chloroform)Example 48 ((IR, cis, ΔΖ) -2,2-dimethyl-5- (5-se c, -butoxy-3-oxo-1-propenyl) -cyclopropane-1-oreboxylic acid (3-propyn) -2-yl-2,5-dioxoimide azolidinedyl) methyl ester, n + 16.5 µl + 1 ° (c = 0, S $, chloroform)
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Eksempel 49.Example 49.
(IR, cis, ΔΖ )-2.2-dimeth.vl-3-( 3-methoxy-3-oxo-l-propenyl)-cyclo-propan-l-carboxylsyre-(S )-cyan-3-phenoxy-4-f luor phen.ylmethyl-ester, 5 dj = +66,5° +2,5° (c = 0,5$, benzen)(IR, cis, ΔΖ) -2,2-Dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid (S) -cyan-3-phenoxy-4- fluorophenylmethyl ester, 5 dj = + 66.5 ° + 2.5 ° (c = 0.5 $, benzene)
Eksempel 50.Example 50
(IR. cis, ΔΖ )-2.2-dime th.vl-3-( 3-me thoxy-3-oxo-l-propenyl )-c.vg1o-propan-l-c ar boxy Is .vre -(RS)-1-(4-fluo r-3 -phenoxy ph eny 1) -2 -pro -10 Pvn-1-.v lester.(IR. Cis, ΔΖ) -2,2-dime thyl-3- (3-methoxy-3-oxo-1-propenyl) -cyclo-propane-1-yl acid - (RS) -1 - (4-fluoro-3-phenoxyphenyl) -2-pro-10 Pvn-1-yl ester.
E.M.E., CEC15: - toppe fra 1,22 til 1,32 ppm, som tilskrives hydrogenatomerne i tvillingmetkylgrupperne, - toppe ved 1,09 - 2,05 og fra 3,1 til 3,43 ppm, som tilskrives 15 hydrogenatomerne i 1- og 3-stillingen i cyclopropyl, - toppe fra 2,62 til 2,66 ppm, som tilskrives hydrogenet i =CH, - toppe ved 3,72-3,73 ppm, som tilskrives hydrogenatomerne i C02-CH3, - toppe fra 5,8 til 6 ppm, som tilskrives det ethyleniske hy-20 drogen (estersiden), - toppe fra 6,38 til 6,83 ppm, som tilskrives det ethyleniske hydrogen (cyciopropylsiden) og hydrogenet i 002-0Ε2 - toppe fra 6,9 til 7,55 ppm, som tilskrives hydrogenatomerne i de aromatiske ringe.EME, CEC15: - peaks from 1.22 to 1.32 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.09 - 2.05 and from 3.1 to 3.43 ppm attributed to the hydrogen atoms in 1- and the 3-position in cyclopropyl, - peaks from 2.62 to 2.66 ppm, which are attributed to the hydrogen i = CH, - peaks at 3.72 to 3.73 ppm, which are attributed to the hydrogen atoms in CO2-CH3, - peaks from 5 , 8 to 6 ppm attributed to the ethylenic hydrogen (ester side), - peaks of 6.38 to 6.83 ppm attributed to the ethylenic hydrogen (cyciopropyl side), and the hydrogen of 002-0Ε2 - peaks of 6.9 to 7.55 ppm, which is attributed to the hydrogen atoms in the aromatic rings.
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Eksempel 51.Example 51.
(lR.cis.AZ)-2.2-dimeth.yl-3-(3-(l.l-dimethylethoxy )-3-oxo-l--propenyl)-cyclopropan-l-carboxylsyre-(ES)-l-(4-fluor-3~Phen-ocyphenyl)-2-prop.yn-l-ylester.(1R.cis.AZ) -2,2-dimethyl-3- (3- (11-dimethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid (ES) -1- (4- fluoro-3-phen ~ ocyphenyl) -2-prop.yn-l-yl ester.
30 N.M.R., CECl*:30 N.M.R., CECl *:
SS
- toppe fra 1,22 til 1,31 ppm, som tilskrives hydrogenatomeme i tvillingmethylgrupperne, - toppe ved 1,47-1,5 ppm, som tilskrives hydrogenatomerne i tert.-butyl, 35 - toppe veo 1,87-2,01 og fra 3,12 til 3,43 ppm, som tilskrives hydrogenatomerne i 1- og 3-stillingen i cyclopropyl, - toppe fra 2,6 til 2,65 ppm, som tilskrives hydrogenet i =CH,- peaks from 1.22 to 1.31 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.47-1.5 ppm attributed to the hydrogen atoms in tert-butyl, 35 - peaks veo 1.87 to 2.01 and from 3.12 to 3.43 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl, - peaks from 2.6 to 2.65 ppm attributed to the hydrogen i = CH,
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26 - toppe ved 5,7-5,9 ppm, som tilskrives det ethyleniske hydrogen (esterside), - toppe fra 6,28 til 6,72 ppm, som tilskrives det ethyleniske hydrogen (cyclopropylsiden) og hydrogenet i CI^-CH, 5 - toppe fra 6,91 til 7,55 ppm, som tilskrives hydrogenatomerne i de aromatiske ringe.26 - peaks at 5.7-5.9 ppm attributed to the ethylenic hydrogen (ester side), - peaks from 6.28 to 6.72 ppm attributed to the ethylenic hydrogen (cyclopropyl side) and the hydrogen in C 5 - peaks from 6.91 to 7.55 ppm attributed to the hydrogen atoms in the aromatic rings.
Eksempel 52.Example 52
(IR« c is.ΔZ)-2.2-d ime thy1-3-(5-me thoxy-5-oxo -1-pro peny1)-c yclo-10 propan-l-carboxylsyre-f SS) -l-( 6-phenor.y-2-p.vrid inyl) -2-propyn--1-ylester.(IR «cis.ΔZ) -2,2-dimethyl-3- (5-methoxy-5-oxo-1-propenyl) -cyclo-propane-1-carboxylic acid (SS) -1- ( 6-phenyl-2-pyridinyl-2-propyn-1-yl ester.
E.M.R., CBC^: - toppe fra 1,23 til 1,31 ppm, som tilskrives hydrogenatomerne i tvillingmethylgrupperne, 15 - toppe ved 1,96-2,1 og fra 3,13 til 3,47 ppm, som tilskrives hydrogenatomerne i 1- og 3-stillingen i cyclopropyl, - toppe fra 2,59 til 2,63 ppm, som tilskrives hydrogenet i s=CH, - top ved 3,73 ppm, som tilskrives hydrogenatomerne i COgCH^, - toppe fra 5,78 til 6,02 ppm, som tilskrives det ethyleniske 20 hydrogen (estersiden), - toppe ved 6,3-6,34 ppm, som tilskrives hydrogenet i C02-CH, - toppe fra 6,43 til 6,88 ppm, som tilskrives det ethyleniske hydrogen (cyclopropylsiden), - toppe fra 6,75 til 7,9 ppm, som tilskrives hydrogenatornerne 25 i de aromatiske ringe.EMR, CBC +: - peaks from 1.23 to 1.31 ppm attributed to the hydrogen atoms in the twin methyl groups, 15 peaks at 1.96-2.1 and from 3.13 to 3.47 ppm attributed to the hydrogen atoms in 1 - and 3-position in cyclopropyl, - peaks from 2.59 to 2.63 ppm attributed to the hydrogen ice = CH, - peak at 3.73 ppm attributed to the hydrogen atoms in COgCH 2, - peaks from 5.78 to 6 , 02 ppm attributed to the ethylenic hydrogen (ester side), - peaks at 6.3-6.34 ppm attributed to the hydrogen in CO 2 -CH, - peaks from 6.43 to 6.88 ppm attributed to the ethylenic hydrogen (the cyclopropyl side), - peaks from 6.75 to 7.9 ppm, attributed to the hydrogen atoms 25 in the aromatic rings.
Eksempel 53.Example 53.
(IR. cis« ΔΖ)-2«2-ά imethy 1-5-( 3-(1«1-<3 imethylethoxy )-3-oso-l--propenyl)-cyclopropan-l-carboxylsyre-(BS)-!-(6-Phenoxy-2-py-30 ridinyl)-2-propyn-l-ylester.(IR. Cis «ΔΖ) -2« 2-ηmethyl 1-5- (3- (1 «1- <3imethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid (BS) - (6-Phenoxy-2-pyridinyl) -2-propyn-1-yl ester.
R.M.R., CDC15: - toppe fra 1,24 til 1,32 ppm, som tilskrives hydrogenatomerne .i tvillingmethylgrupperne, - top ved 1,5 ppm, som tilskrives hydrogenatomerne i tert.-bu-35 tyl, - toppe ved 1,93-2,07 og fra 3,13 til 3,46 ppm, som tilskrives hydrogenatomerne i 1- og 3-stillingen i cyclopropyl,RMR, CDC15: - peaks from 1.24 to 1.32 ppm attributed to the hydrogen atoms in the twin methyl groups, - peak at 1.5 ppm attributed to the hydrogen atoms in tert-butyl, - peaks at 1.93- 2.07 and from 3.13 to 3.46 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl,
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27 - toppe fra 2,59 til 2,63 ppm, som tilskrives hydrogenet i ^CH, - toppe fra 5,68 til 5,90 ppm, som tilskrives det ethyleniske hydrogen (estersiden), - toppe ved 6,3-6,34 ppm, som tilskrives hydrogenet i Ci^-CIW, 5 - toppe fra 6,47 til 6,86 ppm, som tilskrives det ethyleniske hydrogen (cyclopropylsiden), - toppe fra 6,75 til 7,9 ppm, som tilskrives hydrogenatomerne i de aromatiske ringe, 1027 - peaks from 2.59 to 2.63 ppm attributed to the hydrogen in 2 CH, - peaks from 5.68 to 5.90 ppm attributed to the ethylenic hydrogen (ester side), - peaks at 6.3-6, 34 ppm attributed to the hydrogen in C1 -C1W, 5 - peaks from 6.47 to 6.86 ppm attributed to the ethylenic hydrogen (cyclopropyl side), - peaks from 6.75 to 7.9 ppm attributed to the hydrogen atoms in the aromatic rings, 10
Eksempel 54, (lR.cis<gAZ)-2.2-dimethyl-5-(5-(l«l-dimethylethoxy)-3-oxo-l-pro- pen.Yl)-cyclopropan-l-carbox.vlsyre-phen.vlmeth.vlester, R.M.R., CDCl^: - toppe fra 1,28 til 1,32 ppm, som tilskrives hydrogenatornerne i tvillingmethylgruppeme, - top ved 1,5 ppm, som tilskrives hydrogenatomerne i tert.-butyl, - toppe ved 1,9-2,04 og fra 3,08 til 3,41 ppm, som tilskrives hydrogenatomerne i 1- og 3-stillingen i cyclopropyl, 20 - top ved 5,15 ppm, som tilskrives hydrogenatomeme i COg-CE^--c6h5, - toppe ved 5,72-5,92 ppm, som tilskrives det ethyleniske hydrogen (estersiden), 25 - toppe fra 6,38 til 6,75 ppm, som tilskrives det ethyleniske hydrogen (cyclopropylsiden), - top ved 7,4 ppm, som tilskrives hydrogenatomerne i den aromatiske ring, 3Q Eksempel 55« (lR.cis,AZ)-2.2-dimethyl-5-(3-(l«l-dimethylethoxy)-3-oxo-l--propenyl )-cyclopropan-l-carboxyls.yre-( 6-phenoxy-2-pyridinyl )--methylester.Example 54, (1R.cis <gAZ) -2,2-dimethyl-5- (5- (1'-dimethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid phenyl - peaks at 1.28 to 1.32 ppm attributed to the hydrogen atoms of the twin methyl groups, - peak at 1.5 ppm attributed to the hydrogen atoms in tert-butyl, - peaks at 1, 9-2.04 and from 3.08 to 3.41 ppm attributed to the hydrogen atoms in the 1- and 3-position in cyclopropyl, 20 - peak at 5.15 ppm attributed to the hydrogen atoms in COg-CE 2 - c6h5, - peaks at 5.72-5.92 ppm attributed to the ethylenic hydrogen (ester side), 25 - peaks from 6.38 to 6.75 ppm attributed to the ethylenic hydrogen (cyclopropyl side), - peak at 7.4 ppm , which is attributed to the hydrogen atoms in the aromatic ring, 3Q Example 55 '(1R.cis, AZ) -2,2-dimethyl-5- (3- (1'-dimethylethoxy) -3-oxo-1-propenyl) cyclopropane 1-carboxylic acid (6-phenoxy-2-pyridinyl) methyl ester.
N.M.R., CDCl^: 35 - toppe ved 1,3-1,32 ppm, som tilskrives hydrogenatomerne i tvillingmethylgrupperne, - top ved 1,51 ppm, som tilskrives hydrogenatomerne i tert.--butyl,N.M.R., CDCl3: 35 - peaks at 1.3-1.32 ppm attributed to the hydrogen atoms in the twin methyl groups, - peak at 1.51 ppm attributed to the hydrogen atoms in tert-butyl,
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28 - toppe ved 1,96-2,11 og fra 3,13 til 3,47 ppm, som tilskrives hydrogenatomerne i 1- og 3-stillingen i cyclopropyl, - top ved 5,13 ppm, som tilskrives hydrogenatomerne i CC^-CEg-, - toppe ved 5,73-5,92 ppm, som tilskrives det ethyleniske hy-5 drogen (estersiden), - toppe fra 6,37 til 6,73 ppm, som tilskrives det ethyleniske hydrogen (cyclopropylsiden), - toppe ved 7,58-7,72-7,85 ppm, som tilskrives hydrogenatomerne i pyridyIringen, 1028 - peaks at 1.96-2.11 and from 3.13 to 3.47 ppm attributed to the hydrogen atoms in the 1- and 3-position in cyclopropyl, - peak at 5.13 ppm attributed to the hydrogen atoms in CC CEg - peaks at 5.73-5.92 ppm attributed to the ethylenic hydrogen (ester side), - peaks from 6.37 to 6.73 ppm attributed to the ethylenic hydrogen (cyclopropyl side), - peaks at 7.58-7.72-7.85 ppm attributed to the hydrogen atoms in the pyridyl ring, 10
Eksempel 56« (lE,cis.AZ)-2,2-dimethyl-5-(5-methoz.v-3-oxo-l-propenyl)-c.volo- propan-l-carhoxylsyre-(6-phenoxy-2-pyridinyl)-methylester.Example 56 «(1E, cis.AZ) -2,2-Dimethyl-5- (5-methoxy-3-oxo-1-propenyl) -cvolo-propane-1-carboxylic acid (6-phenoxy) 2-pyridinyl) methyl ester.
CDC13: 15 - top ved 1,3 ppm, som tilskrives hydrogenatomerne i tvilling-methylgrupperne, - toppe ved 1,98-2,13 og fra 3,13 til 3,45 ppm, som tilskrives hydrogenatomerne i 1- og 3-stillingen i cyclopropyl, - top ved 3,74 ppm, som tilskrives hydrogenatomerne i COg-CE^, 20 - top ved 5,12 ppm, som tilskrives hydrogenatomerne i COg-C^-, - toppe ved 5,82-6,02 og fra 6,5 til 6,87 ppm, som tilskrives de ethyleniske hydrogenatomer, - toppe fra 7 til 7,85 ppm, som tilskrives hydrogenatomerne i de aromatiske ringe.CDC13: 15 - peak at 1.3 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.98-2.13 and from 3.13 to 3.45 ppm attributed to the hydrogen atoms at the 1 and 3 positions in cyclopropyl, - peak at 3.74 ppm, which is attributed to the hydrogen atoms in COg-CE ^, 20 - peak at 5.12 ppm, which is attributed to the hydrogen atoms in COg-C2 -, - peaks at 5.82-6.02 and from 6.5 to 6.87 ppm attributed to the ethylenic hydrogen atoms; peaks from 7 to 7.85 ppm attributed to the hydrogen atoms in the aromatic rings.
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Eksempel 57.Example 57.
(IB« cis,ΔΖ)-2.2-d imethyl-5-(3-(1.1-d imethylethoxy)-3-oxo-l-Pro- penyl )-cyclopropan-l-carhoxylsyre-( RS)-!-(6-phenox.y-2-p.yri- dinyl)-eth.vlester.(IB, cis, ΔΖ) -2,2-dimethyl-5- (3- (1,1-dimethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid (RS) - (6) -phenoxyl-2-pyridinyl) ethyl ester.
30 R.M.R., CEC15: - toppe fra 1,25 til 1,32 ppm, som tilskrives hydrogenatomerne i tvillingmethylgrupperne, - toppe ved 1,47-1,57 ppm, som tilskrives hydrogenatomerhe i C0p-CH-** » % 3530 R.M.R., CEC15: - peaks from 1.25 to 1.32 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.47-1.57 ppm attributed to hydrogen atoms in COP-CH - ** »% 35
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29 - top ved 1,5 ppm» som tilskrives hydrogenatomerne i tert.-bu- tyl, - toppe ved 1,95-2,09 og fra 5,12 til 5,43 ppm, som tilskrives hydrogenatomerne i 1- og 3-stillingen i cyclopropyl, 5 - toppe fra 5,63 til 5,97 ppm, som tilskrives hydrogenet i C02-CHm, - toppe fra 5,67 til 5,92 og fra 6,32 til 6,75 ppm, som tilskrives de ethyleniske hydrogenatoaer, - toppe fra 6,67 til 7,5 ppm, som tilskrives hydrogenatomerne 10 i de aromatiske ringe, - toppe fra 7,55 til 7,83 ppm, som tilskrives hydrogenatomerne i pyridylringen.29 - peak at 1.5 ppm »attributed to the hydrogen atoms in tert-butyl, - peaks at 1.95-2.09 and from 5.12 to 5.43 ppm attributed to the hydrogen atoms in 1- and 3- the position in cyclopropyl, 5 - peaks from 5.63 to 5.97 ppm attributed to the hydrogen in CO 2 -CHm, - peaks from 5.67 to 5.92 and from 6.32 to 6.75 ppm attributed to the ethylenic hydrogen atoms, - peaks from 6.67 to 7.5 ppm attributed to the hydrogen atoms 10 in the aromatic rings, - peaks from 7.55 to 7.83 ppm attributed to the hydrogen atoms in the pyridyl ring.
Eksempel 58.Example 58
15 (IR« cis , Δ2 )-2«2-dimethyl-5-( 5-methoxy-5-oxo-l-Propen.yl)-cyolo- propan-l-carboxylsyre-(HS)-l-(6-phenoxy-2-pyridinyl)-ethylester. CECl^: - toppe fra 1,25 til 1,3 ppm, som tilskrives hydrogenatomerne i tvillingmethylgrupperne, 20 - toppe fra 1,43 til 1,57 ppm, som tilskrives hydrogenatomerne i C02-CH-c » i % - toppe ved 1,97-2,11 og fra 3,1 til 3,42 ppm, som tilskrives hy-25 drogenatomerne i 1- og 3-stillingen i cyclopropyl, - toppe fra 5,63 til 6,08 ppm, som tilskrives hydrogenet i OOp-CHr', ^ i _ - toppe fra 5,78 til 6,02 og fra 6,45 til 6,87 ppm, son til-30 skrives de ethyleniske hydrogenatomer, - toppe fra 6,67 til 6,8 og fra 7 til 7,67 ppm, som tilskrives hydrogenatomerne i de aromatiske ringe, - toppe fra 7,55 til 7,83 ppm, son tilskrives hydrogenatomerne i pyridyl.(IR) cis, Δ2) -2 '2-Dimethyl-5- (5-methoxy-5-oxo-1-propyl) -cyclopropane-1-carboxylic acid (HS) -1- (6- phenoxy-2-pyridinyl) -ethyl ester. CEC1: - peaks from 1.25 to 1.3 ppm attributed to the hydrogen atoms in the twin methyl groups, 20 - peaks from 1.43 to 1.57 ppm attributed to the hydrogen atoms in CO 2 -CH-c »i% - peaks at 1 , 97-2.11 and from 3.1 to 3.42 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl, - peaks from 5.63 to 6.08 ppm attributed to the hydrogen in OOp -CH 2, - peaks from 5.78 to 6.02 and from 6.45 to 6.87 ppm, are attributed to the ethylenic hydrogen atoms, - peaks from 6.67 to 6.8 and from 7 to 7.67 ppm attributed to the hydrogen atoms in the aromatic rings, - peaks from 7.55 to 7.83 ppm, attributed to the hydrogen atoms in pyridyl.
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Eksempel 59« (IR. cis«ΔΖ )-2. 2-dimethy1-3-(3-(1«1-dimethylethoxy)-3-oxo-l--propeny1) -cyclopropan-l-carboxylsyre-( 3-( phenylcarbonyl) --phenvl)-methylester.Example 59 «(IR. Cis« ΔΖ) -2. 2-dimethyl-3- (3- (1'-dimethylethoxy) -3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid (3- (phenylcarbonyl) -phenyl) -methyl ester.
5 Analyse: C27K30°5 = 434,537 beregnet: C % 74,63 H% 6,96 fundet: 74,60 7,00Analysis: C27K30 ° 5 = 434.537 calculated: C% 74.63 H% 6.96 found: 74.60 7.00
Eksempel 60.Example 60
10 (IS, cis. ΔΖ) -2,2-dimethyl-3-( 3-tert.-butoxy-3-oxo-l-propen.y 1) - -o.yclopropan-l-carboxyl5.yre-lR-(5-Phenox.yphenyl)-2-prop.yn--1-ylestsr.(IS, cis. ΔΖ) -2,2-dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) -1-cyclopropane-1-carboxylic acid 1-R (5-Phenox.yphenyl) -2-prop.yn - 1-ylestsr.
Oq = +58° +1,5° (c = 1,2%, chloroform) 15 Eksempel 61.Oq = + 58 ° + 1.5 ° (c = 1.2%, chloroform) Example 61.
(lH.cis.-AZ)-2.2-dimethyl-3-(3-oyclopropylmethoxy-3-oxo-l-Pi,o-penyl )-cyolopropancarboxy Is yre-(l?L)-(3-Phenox,yphenyl Methyl-ester, - +121° +3° (c = 0,6%, chloroform) 20(1H.cis.-AZ) -2,2-dimethyl-3- (3-oyclopropylmethoxy-3-oxo-1-pi, o-penyl) -cyolopropanecarboxylic acid (1L) - (3-Phenox, yphenyl methyl) -ester, - + 121 ° + 3 ° (c = 0.6%, chloroform) 20
Eksempel 62.Example 62
(IR,cis.ΔΖ)-2,2-dimetby1-3-(3-cyclopropyImethoxy-3-oxo-1--propenyl)-c.yclopropanoarboxyls.vre-(5-PXQP.yn-2-yl-2.5-dioxo-imidazolidinyl)-methylester.(IR, cis.ΔΖ) -2,2-dimetby1-3- (3-cyclopropyImethoxy-3-oxo-1 - propenyl) -c.yclopropanoarboxyls.vre- (5-PXQP.yn-2-yl-2.5- dioxo-imidazolidinyl) methyl ester.
25 ajj = +14° +2° (c = 0,5%, chloroform)Ajj = + 14 ° + 2 ° (c = 0.5%, chloroform)
Eksempel 63« (IR. cis. ΔΖ )-2.2-dimethyl-5-(3-cyclopropylmethox.y-3-oxo-l-Pro-peny 1) -cyclopropancarboxy Is y re -(IB) - (3 -phenoxypheny 1) -2 -pr o-30 P.yn-l-y lester.Example 63 "(IR. Cis. ΔΖ) -2,2-Dimethyl-5- (3-cyclopropylmethoxy) -3-oxo-1-propenyl) cyclopropanecarboxylic acid - (IB) - (3-phenoxyphenyl) ) -2 -pr o-30 P.yn-ly lester.
α-Q = +46° +2° (c = 0,5%, chloroform)α-Q = + 46 ° + 2 ° (c = 0.5%, chloroform)
Eksempel 64« (IR. cis, ΔΖ) -2«2 -d imethy 1-3- (3-n-butox.y-3--oxo-l~propen.yl) -35 ~cyclopropancarbox.yls.yre~(3-propyn-2-yl-2<5-dloxoimidazol-> idinyl)-methylester, a-rj = +17° +1° (c = 1%, chloroform)Example 64 "(IR, cis, ΔΖ) -2" 2-Dimethyl 1-3- (3-n-butoxyl-3-oxo-1-propenyl) -35-cyclopropanecarboxyl acid (3-propyn-2-yl-2 <5-dloxoimidazole-> idinyl) methyl ester, α-rj = + 17 ° + 1 ° (c = 1%, chloroform)
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Eksempel 65« (IR, ois«ΔΖ )-2,2-dime thyl-3-( 3-e thoxy-3-oxo-l--propen.vl) -cyclo-propancarbox.vlsyre~(S )-c.yan-(5~Pheno3:y--4-i‘luorghen.vl)-methyl-ester.Example 65 (IR, αis) ΔΖ) -2,2-Dimethyl-3- (3-thoxy-3-oxo-1-propenyl) cyclo-propane carboxylic acid ~ (S) -c. yan- (5 ~ Pheno3: y - 4-i'luorghen.vl) methyl ester.
5 = +47,5° +2° (c = 0,5$, chloroform)+ 47.5 ° + 2 ° (c = 0.5 $, chloroform)
Eksempel 66, (lR.cis.AZ)-2.2-diineth.vl-5-v3-isopropoxy-3“Oxo-l-propenyl)--oyclopropancarboxylsyre-(S)-cyan-(3-phenoxy-4-fluorphenyl)-10 -meth.vlester, <Xp = +50° +2° (c = 0,3$, chloroform)Example 66, (1R.cis.AZ) -2,2-dimethyl-5-yl-isopropoxy-3-oxo-1-propenyl) oyclopropane carboxylic acid (S) -cyan- (3-phenoxy-4-fluorophenyl) -10-methyl ester, <Xp = + 50 ° + 2 ° (c = 0.3 $, chloroform)
Eksempel 67.Example 67
(IR. cis.ΔΖ)-2.2-d ime th,vl-3-( 3 -cyclopropylme thoxy-3-oxo-l-pro -15 penvl)-cyclopropancarboxyls.yre-(S)-cyan-(3-phenoxy-4-fluor-phenyl)-methylester. ou = +53° (c - 0,25$, chloroform)(IR. Cis.ΔΖ) -2,2-dimethyl, 3- (3-cyclopropylmethoxy-3-oxo-1-prop-phenyl) -cyclopropanecarboxylic acid (S) -cyan- (3-phenoxy) -4-fluoro-phenyl) -methyl ester. ou = + 53 ° (c - 0.25 $, chloroform)
Eksempel 68.Example 68.
20 (IH. cis.ΔΖ)-2,2-d imethyl-3-(3-tert.-butoxy-3-oxo-l-propenyl)- -cyclopropancarboxylsyre-( 2.3.4.5.6-pentaf luorphenyl )-me th.vl-sster.(1H, cis.ΔΖ) -2,2-dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid (2.3.4.5.6-pentafluorophenyl) -me th.vl-sister.
aD. = +37,5° +1,5° (c = 1$, chloroform) 25 Eksempel 69.aD. = + 37.5 ° + 1.5 ° (c = 1 $, chloroform) Example 69.
C IR.cis.ΔΖ)-2.2-dimethy1-3-(3-tert.-butoxy-3-oxo-l-propenyl)--cy clo propancarboxylsy re-(3-Phenoxy-4-fluorphenyl)-me thylester. αΰ = +55,5° +2,5° (c = 0,5$, chloroform) 30 Eksempel 70.C IR.cis.ΔΖ) -2,2-Dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) -cyclo-propanecarboxylic acid (3-Phenoxy-4-fluorophenyl) methyl ester. αΰ = + 55.5 ° + 2.5 ° (c = 0.5 $, chloroform) Example 70.
(lR.cis.AZ)-2.2-dimetfcyl-5-(3-methoxy-3-oxo-l-propenyl)-eyclo-propapcarboxylsyre-(5-Phenoxy-4-fluorphenyl)-methylester. α-p = +50,5° +2,5° (c = 0,55$, chloroform) 1(LR.cis.AZ) -2.2-dimetfcyl-5- (3-methoxy-3-oxo-l-propenyl) -eyclo-propapcarboxylsyre- (5-Phenoxy-4-fluorophenyl) methyl ester. α-β = + 50.5 ° + 2.5 ° (c = 0.55 $, chloroform) 1
Eksempel 71.Example 71.
(lR.cis.AZ)-2.2-dimethyl-3-(3-tert.-butoxy-3-oxo-l-propenyl)--cyclopropancarboxylsyre-(lRS)-(3-phenoxy-4-fluorphenyl)-eth.vlester.(LR.cis.AZ) -2.2-dimethyl-3- (3-tert-butoxy-3-oxo-l-propenyl) - cyclopropanecarboxylic acid (LR S) - (3-phenoxy-4-fluorophenyl) eth. yl ester.
TT TiT *D Λ*ΠΠΊ ·TT TiT * D Λ * ΠΠΊ ·
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32 - toppe fra 1,19 til 1,28 ppm, som tilskrives hydrogenatomerne i tvillingmethylgrupperne, - toppe ved 1,48-1,5 ppm, som tilskrives hydrogenatomerne i tert.-butyl, 5 - toppe fra 1,41 til 1,53 ppm, som tilskrives hydrogenatomerne i C09-CH ^ » qe3 - toppe ved 1,85-1,99 og fra 3,07 til 3,38 ppm, som tilskrives hydrogenatomerne i 1- og 3-stillingen i cyclopropyl, - toppe fra 5,58 til 6 og fra 6,27 til 6,7 ppm, som tilskrives de ethyleniske hydrogenatomer, - toppe fra 6,27 til 6,7 ppm, som tilskrives hydrogenatomet i COp-OHn32 - peaks from 1.19 to 1.28 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks at 1.48-1.5 ppm attributed to the hydrogen atoms in tert-butyl, 5 - peaks from 1.41 to 1, 53 ppm, which is attributed to the hydrogen atoms in CO 9 -CH 2 qe 3 - peaks at 1.85-1.99 and from 3.07 to 3.38 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl, - peaks from 5.58 to 6 and from 6.27 to 6.7 ppm attributed to the ethylenic hydrogen atoms, peaks from 6.27 to 6.7 ppm attributed to the hydrogen atom in COp-OHn
b Ib I
15 - toppe fra 6,92 til 7,53 ppm, som tilskrives hydrogenatomer ne i de aromatiske ringe.15 - peaks from 6.92 to 7.53 ppm, which are attributed to hydrogen atoms in the aromatic rings.
Eksempel 72.Example 72
(IR.cis.AZ)-2.2-diiaethyl-5-(5-methoxy-5-oxo-l-propenyl)-cyolo-20 propancarboxylsyre-(lBS )-(3-Phenox.v-4-fluorphenyl)-ethylester. CSC13: - toppe fra 1,19 til 1,29 ppm, som tilskrives hydrogenatomerne i tvillingmethylgrupperne, - toppe fra 1,41 til 1,54 ppm, som tilskrives hydrogenatomerne 25 i CO/p-GH-, ^ t c% - toppe ved 1,87-2,02 og fra 3,07 til 3,22 ppm, som tilskri-ved hydrogenatomeme i 1- og 3-stillingen i cyclopropyl, 30 - toppe fra 5,82 til 6,17, som tilskrives hydrogenatomet i COp-CHr» c » - toppe fra 5,93 til 6,2 og fra 6,58 til 7 ppm, som tilskrives de ethyleniske hydrogenatomer, 35 _ toppe fra 7,03 til 7,72 ppm, som tilskrives hydrogenatomerne i de aromatiske ringe.(IR.cis.AZ) -2,2-Diaethyl-5- (5-methoxy-5-oxo-1-propenyl) -cyclopropanecarboxylic acid (1BS) - (3-Phenoxy-4-fluorophenyl) ethyl ester . CSC13: - peaks from 1.19 to 1.29 ppm attributed to the hydrogen atoms in the twin methyl groups, - peaks from 1.41 to 1.54 ppm attributed to the hydrogen atoms 25 in CO / p-GH-, tc% - peaks at 1.87-2.02 and from 3.07 to 3.22 ppm attributed to the hydrogen atoms at the 1- and 3-position in cyclopropyl, 30 peaks from 5.82 to 6.17 attributed to the hydrogen atom in CO -CHr "c" - peaks from 5.93 to 6.2 and from 6.58 to 7 ppm attributed to the ethylenic hydrogen atoms, 35 peaks from 7.03 to 7.72 ppm attributed to the hydrogen atoms in the aromatic rings .
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Eksempel 73« (IR, cis. ΔΖ) -2,2-d imethyl-3-( 3-tert«-butoxy-5-oxo-l-propenyl) - -cyclopropancarboxylsyre-5-benzyl-5-furylmethylester.Example 73 (IR, cis. ΔΖ) -2,2-dimethyl-3- (3-tert-butoxy-5-oxo-1-propenyl) -cyclopropane carboxylic acid 5-benzyl-5-furyl methyl ester.
aD = +54,5° +1,5° (c - 1$, chloroform) 5aD = + 54.5 ° + 1.5 ° (c - 1 $, chloroform) 5
Eksempel 74« (IR. cis. ΔΖ) - 2«2-d ime thyl-3-( 3-tert, -butoxy-3-oxo-( 1-propenyl) --cyclopropancarboxylsyre-(lS )-2-methyl-4.-oxo-3-(2-propenyl)--cyclopénten-l-ylester.Example 74 "(IR. Cis. ΔΖ) - 2" 2-Dimethyl-3- (3-tert-butoxy-3-oxo- (1-propenyl) -cyclopropanecarboxylic acid (1S) -2-methyl) 4-oxo-3- (2-propenyl) - cyclopenten-l-yl ester.
10 aj) ~ +73° (c = 0,25$, chloroform)+ 73 ° (c = 0.25 $, chloroform)
Eksempel 75.Example 75
(IR. cis. ΔΖ) -2.2-3imetfay1-5-(3-me thoxy-5-oxo-1-propenyl)-cyclo-propancarboxylsyre-(2-?henoxy-5-thiazolyl)-methylester.(IR. Cis. ΔΖ) -2,2-3-dimethyl-5- (3-methoxy-5-oxo-1-propenyl) -cyclopropanecarboxylic acid (2-henoxy-5-thiazolyl) methyl ester.
15 smp.62°C, α-p = +60,5° +1,5° (c = 1,5$, benzen)Mp 62 ° C, α-β = + 60.5 ° + 1.5 ° (c = 1.5 $, benzene)
Eksempel 76.Example 76
(IR.cis.ΔΖ)-2,2-d ime th.yl-3-(3-methox.v-3-oxo-l-propenyl)-oyclo-20 Propancarbox.vlsyre~(RS )-thioamidophenoxyphenylmethylester.(IR.cis.ΔΖ) -2,2-dimethyl-3- (3-methoxy-3-oxo-1-propenyl) -oyclo-propanecarboxylic acid ~ (RS) -thioamidophenoxyphenylmethyl ester.
I. R. spektrum: - absorptioner ved 1652 cm"1 (C=C) 3475-3365 cm"1 (0=3) t m0 25 i 1713-1736 cm"1 (0=0) H.M.R,, CEClj: - toppe ved 1,25-1,27-1,30 ppm, som tilskrives hydrogenatomerne i tvillingnethylgrupperne, 30 - toppe ved 1,97-2,11 ppm, som tilskrives hydrogenatomet i 1-stillingen i cyclopropyl, - toppe ved 3,08-3,43 ppm, som tilskrives hydrogenatomet i 3-stillingen i cyclopropyl, - toppe ved 3,69-3,72 ppm, som tilskrives hydrogenatomerne i 35 methylgruppen i methoxycarbonyl, - toppe ved 5,73-5,92 ppm og 5,8-5,99 ppm, som tilskrives det ethyleniske hydrogenatom i α-stillingen til C02~CH^,IR spectrum: - absorptions at 1652 cm -1 (C = C) 3475-3365 cm -1 (0 = 3) t m0 25 in 1713-1736 cm -1 (0 = 0) HMR, CEClj: - peaks at 1 , 25-1.27-1.30 ppm attributed to the hydrogen atoms in the twin ethyl groups, 30 - peaks at 1.97-2.11 ppm attributed to the hydrogen atom at the 1-position in cyclopropyl, - peaks at 3.08-3, 43 ppm attributed to the hydrogen atom at the 3-position in cyclopropyl, - peaks at 3.69-3.72 ppm attributed to the hydrogen atoms in the methyl group in methoxycarbonyl, - peaks at 5.73-5.92 ppm and 5.8- 5.99 ppm, which is attributed to the ethylenic hydrogen atom at the α position of CO 2 ~ CH 2,
DK 163918 BDK 163918 B
34 - toppe ved β,32-6,66 ppm, som tilskrives det ethyleniske hydrogenatom i 1-stillingen i -CC^-CH^,34 - peaks at β, 32-6.66 ppm attributed to the ethylenic hydrogen atom at the 1-position of -CC
“ top ved 6,42 ppm, som tilskrives hydrogenet, som er bundet til det carbonatom, som bærer gruppen -C-HH“Peak at 6.42 ppm, which is attributed to the hydrogen bonded to the carbon atom bearing the group -C-HH
5 ' i5 'i
Eksempel 77.Example 77
(IR« cis«ΔΖ) -2«2-d imethyl-3-( 3-tert« -butoxy-5-oxo-l-propenyl) --cyclopropancarboxylsyre-(2-pnenoxy-5-thiazolyl)-methylester. α-jj = +68° +1,5° (c = 1$, chloroform)(IR) cis ΔΖ) -2 "2-Dimethyl-3- (3-tert" -butoxy-5-oxo-1-propenyl) -cyclopropane carboxylic acid (2-phenyl-5-thiazolyl) methyl ester. α-jj = + 68 ° + 1.5 ° (c = 1 $, chloroform)
Eksempel 78.Example 78
(lR.cis.AZ)-2.2-dimethyl-5-(5-methoxy-3-oxo-l-propenyl)-cyclo-propancarboxylsyre-iRS)-oyan-(2-phenoxy-5-thiazolyl)-methyl- 15 j.(1R.cis.AZ) -2,2-dimethyl-5- (5-methoxy-3-oxo-1-propenyl) -cyclo-propanecarboxylic acid (IRS) -oyan- (2-phenoxy-5-thiazolyl) -methyl-methyl j.
ester« oc-j-j = +60° +2° (c = 1$, chloroform)ester «oc-j-j = + 60 ° + 2 ° (c = 1 $, chloroform)
Eksempel 79.Example 79
(1 E« cis «ΔΖ)-2« 2-d imethyl-3-( 3-tert ,-butoxy-3-oxo-l-propenyl)--cyclopropancarbox.ylsyre-( RS )-oyan-(2-phenoxy-5-thiazolyl)--methylester.(1 E "cis" Δ -2) -2 "2-Dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) cyclopropanecarboxylic acid (RS) -oyan- (2-phenoxy) -5-thiazolyl) -, methyl ester.
otjj = +65° +2° (c = 0,5$, chloroform)ojj = + 65 ° + 2 ° (c = 0.5 $, chloroform)
Eksempel 80« (IR-.jaaj3a.AZ) -2«2-åimethyl-5-(5-isopropoxy-5-oxo-l-propenyl)--cyclopropancarboxylsyre-(lR)-3-Phenoxyphenylethylester. a-p = +59° +1,5° (c = 1$, chloroform)Example 80 «(IR- [alpha] az) -2 + 2-dimethyl-5- (5-isopropoxy-5-oxo-1-propenyl) cyclopropane carboxylic acid (1R) -3-Phenoxyphenylethyl ester. α-β = + 59 ° + 1.5 ° (c = 1 $, chloroform)
Eksempel 81.Example 81.
2 Q ~ (IR. cis. ΔΖ )-2.2-dimethyl-3-(3-allyloxy-5-cxo-l-propenyl) --cyclopropancarboxylsyre-l-(R)-(3-Phenoxyphenyl)-ethylester. Trin A: (IR«cis)-2«2-dimethy1-3-(3.3.3-trichlorethoxy-3-oxo-propynyl)-cvclopropancarboxylsyre-tert«-butyles te r.2 Q ~ (IR. Cis. ΔΖ) -2,2-Dimethyl-3- (3-allyloxy-5-cxo-1-propenyl) -cyclopropanecarboxylic acid 1- (R) - (3-Phenoxyphenyl) ethyl ester. Step A: (IR) cis -2-2-Dimethyl-3- (3.3,3-trichloroethoxy-3-oxo-propynyl) -cyclopropanecarboxylic acid tert -butyls.
Man indfører 6,2 g dicyclohexylcarbodiimid i en op- 3 5 løsning indeholdende 7,15 g (IR,cis )-2,2-dimethy1-3-(3-hy-d roxy-3-ox opropyny1)-cyclopropancarboxyIsyre-te rt.-butyle s t e r, fremstillet som angivet i præparation 2 A, og 80 mg dimethyl- 35 ami n opy ri din i 35 ml methylenchlorid. Man omrører reaktions-blandingen i IC minutter og tilsætter 4,5 g 2,2,2-trichIor-ethanol. Man holder under omrøring i 1 time og eliminerer den dannede udfældning ved filtrering. Man vasker filtratet med 5 1 ΙΊ saltsyre og derefter med vand indtil neutralitet, tørrer det og inddamper det til tørhed. Der fås 14 g af en olie, som man chromatograferer på silicagel under eluering med en blanding af benzen og ethylacetat (97*5)* Man isolerer således 9 g af den forventede forbindelse ned smp. 7C-71°C.6.2 g of dicyclohexylcarbodiimide is introduced into a solution containing 7.15 g (IR, cis) -2,2-dimethyl-3- (3-hydroxy-3-oxopropynyl) cyclopropanecarboxylic acid tea rt.-butyl ester, prepared as set forth in Preparation 2A, and 80 mg of dimethylamino amine in 35 ml of methylene chloride. The reaction mixture is stirred for 1 minute and 4.5 g of 2,2,2-trichloroethanol are added. Stir under stirring for 1 hour and eliminate the formed precipitate by filtration. The filtrate is washed with 5 L hydrochloric acid and then with water until neutrality, dried and evaporated to dryness. 14 g of an oil is obtained which is chromatographed on silica gel eluting with a mixture of benzene and ethyl acetate (97 * 5). Thus, 9 g of the expected compound are isolated, m.p. 7C-71 ° C.
10 Trin B: (IR. cis) -2.2-d ime th.vl-5-( 5.5.5 -trichlore thoxy-3-o:xo-propyn.yl )-cyclopropancarboxylsyre.Step B: (IR. Cis) -2,2-dimethyl-5- (5.5,5-trichloro-thoxy-3-o: xo-propynyl) -cyclopropane carboxylic acid.
Kan tilbagesvaler i 1 time en blanding indeholdende 11,4 g af forbindelsen fremstillet ifølge trin A, 120 ml toluen og 300 mg p-toluensulfonsyre. Kan lader genantage stue-15 temperatur og vasker reaktionsblandingen med vand, tørrer den og inddamper den til tørhed. Der fås således 9,5 g af den forventede forbindelse, som man umiddelbart benytter i det følgende trin.Can reflux for 1 hour a mixture containing 11.4 g of the compound prepared according to step A, 120 ml of toluene and 300 mg of p-toluenesulfonic acid. Can recharge room temperature and wash the reaction mixture with water, dry it and evaporate to dryness. Thus, 9.5 g of the expected compound is obtained, which is used immediately in the following step.
Trin C: (15.cis )-2.2-dimeth.71-5-(5.5.5-trichlorethoxy-5-oxo-20 propypyl )-o.vclopropancarboxyls.yre~åja)-(5-Pheaoxy- phenyl)-ethylester.Step C: (15.cis) -2,2-Dimeth.71-5- (5.5.5-Trichloroethoxy-5-oxo-propypyl) ocyclopropanecarboxylic acid () - (5-Pheaoxyphenyl) ethyl ester .
Man blander 6 g af den i trin B opnåede forbindelse, 30 ml methylenchlorid og 600 mg 4-dimethylaminopyridin.6 g of the compound obtained in step B are mixed, 30 ml of methylene chloride and 600 mg of 4-dimethylaminopyridine.
Derpå indfører man langsomt i den således opnåede op-25 løsning ved 0°C under omrøring 3,95 g dicyclohexylcarbodiimid, omrører yderligere 30 minutter, stadig ved 0°C, og tilsætter dråbevis ved samme temperatur en opløsning af 4,1 g 1-(R)--(3-phenoxyphenyl)-ethanol i 12 ml methylenchlorid.Then, slowly, in the solution thus obtained at 0 ° C, stir in 3.95 g of dicyclohexylcarbodiimide, stir for an additional 30 minutes, still at 0 ° C, and add dropwise a solution of 4.1 g of 1- (R) - (3-phenoxyphenyl) ethanol in 12 ml of methylene chloride.
Kan omrører reaktionsblandingen i 17 timer ved stue-30 temperatur og filtrerer. Man inddamper filtratet til tørhed under formindsket tryk. Der fås en olie, som man chromatogra-ferer på silicagel under eluering med cyclohexan og ethyl-acetat (8:2). Der fås 4,4 g af den ønskede forbindelse.May stir the reaction mixture for 17 hours at room temperature and filter. The filtrate is evaporated to dryness under reduced pressure. An oil is obtained which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (8: 2). 4.4 g of the desired compound are obtained.
Trin D: (IR.cis)-2.2-dimethyl-5-(5-hydroxy-3-oxopropynyl)-35 -eyclopropanoarbox.ylsyre-l£-(5-phenoxyphenyl)-ethyl- ester.Step D: (IR.cis) -2,2-Dimethyl-5- (5-hydroxy-3-oxopropynyl) -35-cyclopropanoarboxylic acid -1β- (5-phenoxyphenyl) ethyl ester.
Man indfører under omrøring 0,53 g zinkpulver i en op-0.53 g of zinc powder is introduced into a solution with stirring.
DK 163918BDK 163918B
36 løsning af 4,16 g af den i trin C fremstillede forbindelse i 4 ml methylenchlorid og 45 ml eddikesyre. Man omrører i 30 minutter ved stuetemperatur og tilsætter derpå atter 0,53 g zinkpulver. Man gentager denne operation yderligere 2 gange 5 og eliminerer derefter ved filtrering det resterende zink, som man skyller med 40 ml vand og 100 ml methylenchlorid.36 solution of 4.16 g of the compound prepared in step C in 4 ml of methylene chloride and 45 ml of acetic acid. The mixture is stirred for 30 minutes at room temperature and then 0.53 g of zinc powder is added again. This operation is repeated two more times 5 and then, by filtration, the remaining zinc which is rinsed with 40 ml of water and 100 ml of methylene chloride is eliminated.
Man ekstraherer med methylenchlorid. Man vasker, tørrer og inddamper til tørhed under formindsket tryk. Der fås således 3,05 g af den forventede forbindelse.Extract with methylene chloride. Wash, dry and evaporate to dryness under reduced pressure. Thus, 3.05 g of the expected compound are obtained.
10 Trin Bt (lR.ois.AZ)-2.2-dimethyl-3-(5-hydroxy-3-oxo-l-prope-nyl)-cyciopropanoarboxylsyre-l-(R)-(3-Phenoxyphenyl)--ethylester.Step Bt (1R.ois.AZ) -2,2-dimethyl-3- (5-hydroxy-3-oxo-1-propenyl) -cyciopropanoarboxylic acid 1- (R) - (3-Phenoxyphenyl) ethyl ester.
Man foretager en hydrogenering af 3 g af den i forrige trin fremstillede forbindelse i 80 ml ethylacetat i nærværei-15 se af 500 mg palladiumhydroxid (10$ på bariumsulfat) og 0,9 ml quinolin. Man filtrerer og vasker filtratet med saltsyre og derefter med vand. Man tørrer og inddamper til tørhed under formindsket tryk. Der fås således 2,9 g af den forventede forbindelse, 20 Trin Pi (lR.cis.AZ)-2.2-dimethyl-3-(5-allyloxy-5-oxo-l-prope-ny1)-oyolopronancarboxylsyre-1-(R)-(3-phenoxyphenyl)--ethylester.Hydrogenation of 3 g of the compound of the previous step is carried out in the presence of 80 ml of ethyl acetate in the presence of 500 mg of palladium hydroxide ($ 10 on barium sulfate) and 0.9 ml of quinoline. The filtrate is filtered and washed with hydrochloric acid and then with water. Dry and evaporate to dryness under reduced pressure. Thus, 2.9 g of the expected compound, 20 Step Pi (1R.cis.AZ) -2,2-dimethyl-3- (5-allyloxy-5-oxo-1-prope-nyl) -oyolopronanecarboxylic acid 1- ( R) - (3-phenoxyphenyl) -, ethyl ester.
Man blander 1,4 g (lR,cis,AZ)-2,2-dimethyl-3*-(3-hy-droxy-3-oxo-l-propenyl)-cyclopropancarboxylsyre-l-(R)-(3-25 -phenoxyphenyl)-ethylester (fremstillet i trin E), 7 ml methylenchlorid og 0,14 g 4-dimethylaminopyridin. Man indfører ved 0°C under omrøring 760 mg dicyclohexylcarbodiimid, omrører yderligere 20 minutter ved 0°C, og ved denne temperatur tilsætter man derpå 0,26 ml allylalkohol i 2 ml methylen- ΟΛ chlorid. Man omrører i 1 time ved stuttemperatur og filtrerer derpå reaktiohsblandingen. Man inddamper filtratet til tørhed under formindsket tryk og får en olie, som man ehromatogra-ferer på silicagel under eluering med hexan og isopropylether (8:2). Der fås 570 mg af den forventede forbindelse, = +109,5° 35 +2° (c = 1$, chloroform).1.4 g (1R, cis, AZ) -2,2-dimethyl-3 * - (3-hydroxy-3-oxo-1-propenyl) -cyclopropanecarboxylic acid 1- (R) - (3- 25-phenoxyphenyl) ethyl ester (prepared in step E), 7 ml of methylene chloride and 0.14 g of 4-dimethylaminopyridine. 760 mg of dicyclohexylcarbodiimide is stirred at 0 ° C, stirred for an additional 20 minutes at 0 ° C, and at this temperature 0.26 ml of allyl alcohol is then added to 2 ml of methylene en chloride. The mixture is stirred at room temperature for 1 hour and then the reaction mixture is filtered. The filtrate is evaporated to dryness under reduced pressure to give an oil which is ehromatographed on silica gel eluting with hexane and isopropyl ether (8: 2). 570 mg of the expected compound are obtained, = + 109.5 ° 35 + 2 ° (c = 1 $, chloroform).
3737
Bksempel 82, (lR+cis,AZ)-2,2-dimethyl-3-(3-tert.-butoxy-3-oxo-l-propenyl)- -cyclopropancarboxylsyre-l-(R)-(3-Phenoxyphenyl)-ethylester.Example 82, (1R + cis, AZ) -2,2-Dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid 1- (R) - (3-Phenoxyphenyl) ethyl ester.
Man indfører under omrøring ved stuetemperatur 1,4 g 5 o-tert.'-butyl-lTjIT'-diisopropylurinstof i en opløsning af I, 74 g (lR,cis,AZ)-2,2-dimethyl-3-(3-hydroxy-3-oxo-l-prope-nyl)-cyclopropancarboxylsyre-l-(R)-(3-phenoxyphenyl)-ethyl-ester (fremstillet efter fremgangsmåden i trin S i eksempel 81) i 8' ml ethylacetat. Lian omrører yderligere 4 timer og 10 filtrerer derpå. Filtratet inddampes til tørhed under formindsket tryk. Ren opnåede forbindelse chromatograferes på silicagel under eluering med hexan og ether (|3:2). Rer fås således 930 mg af den forventede forbindelse med smp. 80°C,While stirring at room temperature, 1.4 g of 5-tert.-butyl-1TjIT'-diisopropylurea are introduced into a solution of 1,74 g (1R, cis, AZ) -2,2-dimethyl-3- (3- hydroxy-3-oxo-1-propanyl) -cyclopropane carboxylic acid 1- (R) - (3-phenoxyphenyl) ethyl ester (prepared according to the procedure of step S of Example 81) in 8 'ml of ethyl acetate. Lian stirs another 4 hours and then filters. The filtrate is evaporated to dryness under reduced pressure. Pure obtained compound is chromatographed on silica gel eluting with hexane and ether (| 3: 2). Thus, 930 mg of the expected compound is obtained with m.p. 80 ° C,
Op +125° +2° (c = Ifo, chloroform), 15At + 125 ° + 2 ° (c = Ifo, chloroform), 15
Sksempel 83.Example 83.
(IR, ci s, ΔΖ) -2,2 -d ime thy1-3-(3-tert.-butoxy-3-oxo-l-propeny1)--cyclopropancarboxylsyre-m-phenoxybenzylester.(IR, cis, ΔΖ) -2,2-dimethyl-3- (3-tert-butoxy-3-oxo-1-propenyl) cyclopropane carboxylic acid m-phenoxybenzyl ester.
Trin A: (IR.cis)-2,2-dimethyl-3-(3.3.3-trichlorethoxy-3-oxo-20 propynyl)-oyolopropancarboxylsyre-m-phenoxybenzyl- ester.Step A: (IR.cis) -2,2-dimethyl-3- (3.3,3-trichloroethoxy-3-oxo-propynyl) -oyolopropane carboxylic acid m-phenoxybenzyl ester.
Man blander 6,7 g (lR,cis)-2,2-dimethyl-3~(3,3,3--trichlorethoxy-3-oxopropynyl)-cyclopropancarboxylsyre (fremstillet ifølge trin B i eksempel 81), 67 ml methylenchlorid 25 og 200 mg 4-dimethylaminopyridin, Man indfører derpå ved 0°0 og under omrøring 4,5 g m-phenoxybenzylalkohol i 5 ml methylenchlorid og derefter en opløsning af 4,4 g dicyclohexyl-carbodiimid i 5 ml methylenchlorid. Man omrører reaktionsblandingen i 3 timer ved stuetemperatur og filtrerer, Man 30 inddamper filtratet til tørhed under formindsket tryk og får II, 5 g af en olie, som man chromatograferer på silicagel linder eluering med cyclohexan og ethylacetat (85*15). Rer fås 7,1 g af den forventede forbindelse.6.7 g (1R, cis) -2,2-dimethyl-3- (3,3,3-trichloroethoxy-3-oxopropynyl) -cyclopropane carboxylic acid (prepared according to step B of Example 81), 67 ml of methylene chloride are mixed. and 200 mg of 4-dimethylaminopyridine are then added at 0 ° and with stirring 4.5 g of m-phenoxybenzyl alcohol in 5 ml of methylene chloride and then a solution of 4.4 g of dicyclohexylcarbodiimide in 5 ml of methylene chloride. The reaction mixture is stirred for 3 hours at room temperature and filtered. The filtrate is evaporated to dryness under reduced pressure to give II, 5 g of an oil which is chromatographed on silica gel, eluting with cyclohexane and ethyl acetate (85 * 15). Rer is available 7.1 g of the expected compound.
Trin B: (lR.cis)-2.2-dimethvl-3-(5-hydroxy-3-oxopropynyl)-35 -cvclopropancarboxylsyre-m-phenoxybenzylester.Step B: (1R.cis) -2,2-Dimethyl-3- (5-hydroxy-3-oxopropynyl) -35-cyclopropane carboxylic acid m-phenoxybenzyl ester.
Man indfører under omrøring 5 g zinkpulver i en opløsning af 5 g af det i trin A fremstillede stof i 18 mlWhile stirring, 5 g of zinc powder is introduced into a solution of 5 g of the substance of step A in 18 ml.
DK 163918 BDK 163918 B
38 eddikesyre og 2 ml vand. Man omrører i 2 timer ved stuetemperatur og eliminerer derefter ved filtrering det resterende zink, som man skyller med vand og derefter med methylen-chlorid, Man vasker den organiske fase med vand, tørrer den 5 og inddamper til tørhed under formindsket tryk. Man optager den fremkomne rest i toluen, som man inddamper til tørhed under formindsket tryk. Denne sidste operation udføres 3 gange. Man får således 3,6 g forbindelse, som man umiddelbart benytter i det næste trin.38 acetic acid and 2 ml of water. The mixture is stirred for 2 hours at room temperature and then, by filtration, the residual zinc which is rinsed with water and then with methylene chloride is removed. The organic phase is washed with water, dried 5 and evaporated to dryness under reduced pressure. The resulting residue is taken up in toluene which is evaporated to dryness under reduced pressure. This last operation is performed 3 times. Thus, 3.6 g of compound is obtained, which is used immediately in the next step.
10 Trin G: (IR,c is)-2,2-d ime thvl-3-(3-tert,-butoxy -3-oxo-propy-nyl) -c yclopropancarboxylsyre-m-phenoxybenzy lester.Step G: (IR, cis) -2,2-dimethyl-3- (3-tert-butoxy-3-oxo-propynyl) -cyclopropanecarboxylic acid m-phenoxybenzyl ester.
Man indfører dråbevis under omrøring ved stuetemperatur 4 ml o-tert.-butyl-U,jF-diisopropylurinstof i 2 g af den i forrige trin opnåede forbindelse. Derpå tilsætter man 25 ml 15 ethylacetat og omrører 1 time. Man ødelægger overskuddet af reagens ved tilsætning af 2 ml eddikesyre og omrører yderligere i 15 minutter. Man filtrerer, skyller med ethylacetat og inddamper filtratet til tørhed. Der fås 2,8 g af en olie, som man renser ved chromatografi på silicagel under eluering med 20 cyclohexan og ethylacetat (8:2). Der fås således 1,4 g af den forventede forbindelse.4 ml of o-tert.-butyl-U, .alpha.-diisopropylurea are added dropwise with stirring at room temperature in 2 g of the compound obtained in the previous step. Then 25 ml of ethyl acetate is added and stirred for 1 hour. The excess reagent is destroyed by the addition of 2 ml of acetic acid and further stirred for 15 minutes. Filter, rinse with ethyl acetate and evaporate the filtrate to dryness. 2.8 g of an oil is obtained which is purified by chromatography on silica gel eluting with 20 cyclohexane and ethyl acetate (8: 2). 1.4 g of the expected compound is thus obtained.
Trin D: (lR.cis.AZ)-2>2-H3imethyl-3-(5-tert.-butoxy-5-oxo-l--propenyl)-cyclopropancarboxylsyre-m-phenoxy-benzyl ester, 25 Man foretager en hydrogenering af 1,4 g af den i for rige trin fremstillede forbindelse i 30 ml ethylacetat i nærværelse af 500 mg palladiumhydroxid (10$ på bariumsulfat) og 0,7 ml quinolin. Man filtrerer, vasker filtratet med 2 Έ saltsyre og med vand, tørrer det og inddamper til tørhed under 30 formindsket tryk. Der fås således en olie, som man renser ved to gange chromatografi på silicagel under eluering med cyclohexan og ethylacetat (9:1 første gang og 95:5 anden gang).Step D: (1R.cis.AZ) -2> 2-H 3 -methyl-3- (5-tert-butoxy-5-oxo-1-propenyl) -cyclopropane carboxylic acid m-phenoxy-benzyl ester hydrogenation of 1.4 g of the compound prepared in rich steps in 30 ml of ethyl acetate in the presence of 500 mg of palladium hydroxide ($ 10 on barium sulfate) and 0.7 ml of quinoline. Filter, wash the filtrate with 2 vas hydrochloric acid and with water, dry it and evaporate to dryness under reduced pressure. Thus, an oil is obtained which is purified by double chromatography on silica gel eluting with cyclohexane and ethyl acetate (9: 1 the first time and 95: 5 the second time).
Der fås således 1 g af den forventede forbindelse, = +38,5° +2,5° (c = 0,5$, benzen).Thus, 1 g of the expected compound is obtained, = + 38.5 ° + 2.5 ° (c = 0.5 $, benzene).
35 3935 39
Eksempel 84.Example 84
(lE.cis.AZ)-2.2-dimeth.yl-3-(3-oxo-5--ethox.v-l-propen.vl)-oycio-propancarboxyls y r e - (5S) -cyan -2 - (6 -ph en oxy p.v r i d y 1) -mg thyle s t e r. Trin A; (ia.cis)-2.2-dimeth.vl-5-(5-03CO-5-methoxypropynyl)-5 -cyclopropancarboxylsyre.(1E.cis.AZ) -2,2-Dimethyl-3- (3-oxo-5-ethoxyl-propenyl) -oycio-propanecarboxylic acid - (5S) -cyan-2- (6-ph an oxy pv ridy 1) -mg thyle ste r Step A; (ia.cis) -2,2-dimethyl-5- (5-03CO-5-methoxypropynyl) -5-cyclopropane carboxylic acid.
Man tilbagesvaler i 1 time 30 minutter en opløsning indeholdende 2,6 g (lB,cis)-2,2-dimethyl-3-(3-oxo-3-methoxy-propynyl)-cyclopropancarboxylsyre-tert.-butylester fremstillet ifølge trin A i præparation 1, 25 mi toluen og 100 mg 10 p-toluensulfgnsyre. Kan lader genantage stuetemperatur, holder reaktionsblandingen under omrøring i 20 timer og inddamper derpå til tørhed under formindsket tryk. Dec fås 1,95 g af den forventede forbindelse.A solution containing 2.6 g of (1B, cis) -2,2-dimethyl-3- (3-oxo-3-methoxy-propynyl) -cyclopropane carboxylic acid tert-butyl ester prepared according to step A is refluxed for 1 hour 30 minutes. in preparation 1, 25 ml of toluene and 100 mg of 10β-toluenesulfonic acid. Can allow to re-enter room temperature, keep the reaction mixture under stirring for 20 hours and then evaporate to dryness under reduced pressure. Dec is obtained 1.95 g of the expected compound.
Trin B: (IB. cis) -2.2-c imeth.vl-3- (3-oxo-3-methox.vpropyny 1) -c.v-15 clopropancarboxylsyre-(55)-2-(6-phenoxypyridyl)methyl- ester.Step B: (IB. Cis) -2,2-cimethyl-3- (3-oxo-3-methoxy-propynyl) -cyclo-propanecarboxylic acid (55) -2- (6-phenoxypyridyl) methyl ester .
Man blander under omrøring og under nitrogenatmosfære en opløsning af 1S,9 g (BS)-cyan-2-(6-phenoxypyridyl)-metha-nol i 75 ml methylenohlorid med en opløsning af 21,6 g (15, 20 cis)-2,2-dimethyl-3-(3-oxo-3-methoxypropynyl)-cyclopropan-carboxylsyre (fremstillet efter foregående trin) i 75 ml me-thylenchlorid. Man indfører derpå ved 5°C 1 g 4-dimethylamino-pyridin og efter opløsning 21 g dicyclohexylcarbodiimid. Man omrører 4 timer ved stuetemperatur. Man filtrerer og inddam-25 per filtratet under formindsket tryk ved 40°C. Man chromato-graferer den opnåede rest på silicagel under eluering med cyciohexan og ethylacetat (7:3). Eer fås således 35,4 g af den forventede forbindelse.A solution of 1S, 9 g (BS) -cyan-2- (6-phenoxypyridyl) -methanol in 75 ml of methylene chloride is mixed with a solution of 21.6 g (15, 20 cis) under stirring and under nitrogen atmosphere. 2,2-dimethyl-3- (3-oxo-3-methoxypropynyl) -cyclopropane-carboxylic acid (prepared after the previous step) in 75 ml of methylene chloride. 1 g of 4-dimethylamino-pyridine is then introduced at 5 ° C and after dissolution 21 g of dicyclohexylcarbodiimide. Stir for 4 hours at room temperature. The filtrate is filtered and evaporated under reduced pressure at 40 ° C. Chromatograph the residue obtained on silica gel eluting with cyciohexane and ethyl acetate (7: 3). Thus, 35.4 g of the expected compound are obtained.
Trin C; (lB.cis)-2.2-aimethyl-5-(3-oxo~3-hydroxypropynyl)-cy-30 clopropancarboxylsyre-(H3)-cyan-2-(6-phenoxypvridyl)- methylester«Step C; (1b.cis) -2,2-dimethyl-5- (3-oxo-3-hydroxypropynyl) -cyclopropanecarboxylic acid (H3) -cyan-2- (6-phenoxypyridyl) methyl ester
Man tilbaresvaler i 24 timer en blanding af 35,4 g af den i forrige trin opnåede forbindelse, 175 ml dioran, 35 ml vand og 5 g p-toluensulfomsyre. Man inddamper opløsnin-35 gen under formindsket tryk og optager resten i 250 ml methy-lenchlorid og 100 ml vand. Man vasker den organiske fase med vand, tørrer og inddamper under formindsket tryk. Man chroma-A mixture of 35.4 g of the compound obtained in the previous step, 175 ml of dioran, 35 ml of water and 5 g of p-toluenesulfonic acid, was refluxed for 24 hours. The solution is evaporated under reduced pressure and the residue is taken up in 250 ml of methylene chloride and 100 ml of water. The organic phase is washed with water, dried and evaporated under reduced pressure. Male chromatic
DK 163918 BDK 163918 B
40 tograferer det fremkomne stof på silioagel under eluering med cyclohexan og ethylacetat (6:4) tilsat 0,1# eddikesyre og får således 17,7 g af den forventede forbindelse.40 trains the resulting substance on silio gel eluting with cyclohexane and ethyl acetate (6: 4) with 0.1 # acetic acid, thus obtaining 17.7 g of the expected compound.
Trin D: (lS.cis.ÅZ)-2.2-dimethyl-3-(5-oxo-3-hyaroxy-l-prope-5 nyl)-cyclopropancarboxylsyre-(SS)-cyan-2-(6-phenoxy- py r id y 1) -me thy le s t e r.Step D: (1S.cis.AZ) -2,2-Dimethyl-3- (5-oxo-3-hyaroxy-1-propenyl) -cyclopropanecarboxylic acid (SS) -cyan-2- (6-phenoxypy) r id y 1) -me thy le ste r.
Man foretager en hydrogenering af 17,7 g af den i forrige trin fremstillede forbindelse i 200 ml ethylacetat i nærværelse af 2,5 g palladiumhydroxid (10# på bariumsulfat) og 10 2,5 ml quinolin ved 20°C. Man filtrerer, tørrer, inddamper til fjernelse af opløsningsmidlet under formindsket tryk og chromatograferer på silioagel under eluering med cyclohexan, ethylacetat og eddikesyre (6:4:0,1). Der fås således 15 g af den forventede forbindelse.Hydrogenation of 17.7 g of the compound prepared in the previous step is carried out in 200 ml of ethyl acetate in the presence of 2.5 g of palladium hydroxide (10 # on barium sulfate) and 10 2.5 ml of quinoline at 20 ° C. Filter, dry, evaporate to remove the solvent under reduced pressure and chromatograph on silica gel eluting with cyclohexane, ethyl acetate and acetic acid (6: 4: 0.1). Thus, 15 g of the expected compound are obtained.
15 Trin E: (lR.cis.AZ)-2^2-dimethyl-5~(5-oxo-3-ethoxy-l-propenyl)--cyclopropancarboxylsyre-(SS)-cyan-2-(6-phenoxypyri-dyl)-methylester.Step E: (1R.cis.AZ) -2β-dimethyl-5- (5-oxo-3-ethoxy-1-propenyl) -cyclopropanecarboxylic acid (SS) -cyan-2- (6-phenoxypyric acid) dyl) methyl ester.
Man indfører under omrøring og under nitrogenatmosfære 70 mg 4-dimethylaminopyridin og derpå 1,13 g dicyclohexylcar-20 bodiimid i en til 0°C afkølet opløsning af 1,95 g (lR,cis,AZ)--2,2-dimethyl-3-(3-oxo-3-hydroxy-l-propenyl)-cyclopropancarb-oxyIsyre-(SS)-cyan-2-(6-phenoxypyrid y1)-me thyles ter (frems tillet som i forrige trin) i 10 ml methylenchlorid og 2 ml ethanol.70 mg of 4-dimethylaminopyridine is added with stirring and under nitrogen, and then 1.13 g of dicyclohexylcarbodiimide in a solution of 1.95 g (1R, cis, AZ) cooled to 2,2-dimethyl-2 3- (3-oxo-3-hydroxy-1-propenyl) -cyclopropanecarboxylic acid (SS) -cyan-2- (6-phenoxypyridyl) methyls (prepared as in previous steps) in 10 ml of methylene chloride and 2 ml of ethanol.
25 Man omrører yderligere 1 time 30 minutter ved stue temperatur, filtrerer, skyller, vasker det uopløselige materiale med methylenchlorid og inddamper til tørhed under formindsket tryk. Man chromatograferer resten på silioagel 2 gange under eluering med cyclohexan og ethylacetat (8:2 første 30 gang og 85:15 anden gang) og får således 1,4 g af den forventede forbindelse, a-p = +48® +2° (c = 0,5#, chloroform).25 Stir for an additional 1 hour 30 minutes at room temperature, filter, rinse, wash the insoluble material with methylene chloride and evaporate to dryness under reduced pressure. The residue is chromatographed on silio gel twice eluting with cyclohexane and ethyl acetate (8: 2 the first time and 85:15 the second time) to give 1.4 g of the expected compound, ap = + 48® + 2 ° (c = 0.5 #, chloroform).
Eksempel 85.Example 85.
(IR.cis.ΔΖ)-2.2-dimethv1-3-(3-OXO-3-isopropyloxy-1-propenyl)-35 -cyclopropancarboxylsyre-(SS)-cyan-2-(6-phenoxypyrid yl)-me- thylester.(IR.cis.ΔΖ) -2,2-Dimethyl-3- (3-OXO-3-isopropyloxy-1-propenyl) -35-cyclopropanecarboxylic acid (SS) -cyan-2- (6-phenoxypyridyl) methyl ester .
Idet man arbejder som i eksempel 84 ud fra 1,95 g 41 (IR,cis,ΔΖ)~2,2-dimethyl-3-(3-oxo-5-hydroxy-l-propenyl)-cy-clopropancarboxylsyre (RS)-cyan-2-(6-phenoxypyridyl)-methyl-ester fremstillet som angivet i trin D i eksempel 84 og 2 ml isopropanol, får man en olie, som man chromatograferer på 5 silicage! under eluering med cyelohexan og ethylacetat (Sil). Der fås således 1,7 g af den forventede forbindelse, = +53° +2° (c = 0,75$, chloroform).Working as in Example 84 from 1.95 g of 41 (IR, cis, ΔΖ) ~ 2,2-dimethyl-3- (3-oxo-5-hydroxy-1-propenyl) -cyclopropane carboxylic acid (RS) -cyan-2- (6-phenoxypyridyl) methyl ester prepared as indicated in step D of Example 84 and 2 ml of isopropanol gives an oil which is chromatographed on 5 silicages! eluting with cyelohexane and ethyl acetate (Sil). Thus, 1.7 g of the expected compound is obtained, = + 53 ° + 2 ° (c = 0.75 $, chloroform).
Eksempel 86.Example 86
10 (IR. cis, ΔΖ) -2«2-dime thyl-3-( 3-oxo-3-c.vclobutox.v-l-propen.yl )--cyclopropancarbox.ylsyre-( RS )-cyan-2-(6-phenoxypyrld.yl )-me-thylester.(IR, cis, ΔΖ) -2- 2-dimethyl-3- (3-oxo-3-cyclobutoxyl-propenyl) cyclopropanecarboxylic acid (RS) -cyan-2- ( 6-phenoxypyridyl) methyl ester.
Idet man arbejder som i eksempel 84 ud fra 2,1 g (IR, cis,ΔΖ)~2,2-dimethyl-3-(3-oxo-3-hydroxy-l-propenyl)-cyclo-15 propancarboxylsyre-(RS)-cyan-2-(6-phenoxypyridyl)-methylester fremstillet som angivet i trin D i eksempel 84 og 1 ml cyclo-butanol, får man en olie, som man chromatograferer på sili-cagel under eluering med hexan og ethylacetat (8:2). Der fås således 1,6 g af den forventede forbindelse, =44,5° +2° 20 (c = 0,5$, benzen).Working as in Example 84 from 2.1 g (IR, cis, ΔΖ) ~ 2,2-dimethyl-3- (3-oxo-3-hydroxy-1-propenyl) -cyclo-propane carboxylic acid (RS) ) -cyan-2- (6-phenoxypyridyl) methyl ester prepared as indicated in Step D of Example 84 and 1 ml of cyclobutanol gives an oil which is chromatographed on silica gel eluting with hexane and ethyl acetate (8: 2). Thus, 1.6 g of the expected compound is obtained, = 44.5 ° + 2 ° 20 (c = 0.5 $, benzene).
Eksempel 87.Example 87
(lH4cis/AZ)-2.2-dimetkyl-3-(5-oxo-3-n-butoxy-l-propenyl)-cy-clopropanearboxylsyre-(ES )-c.yan-2-(6-phenoxypyridyl)-methyl-25 ester.(1H4cis / AZ) -2,2-dimethyl-3- (5-oxo-3-n-butoxy-1-propenyl) -cyclopropanearboxylic acid (ES) -cyan-2- (6-phenoxypyridyl) methyl 25 ester.
Idet man arbejder som i eksempel 84 ud fra 2,1 g (IR, cis,ΔΖ)-2,2-dime thy1-3-(3-oxo-3-hyd roxy-l-propeny1)-cyclopro-pancarboxylsyre-(RS)-cyan-2-(6-phenoxypyridyl)-methylester fremstillet som angivet i trin D i eksempel 84 og 1 ml n-bu-30 tanol, får man en olie, som man chromatograferer på silicagel under eluering med n-hexan og ethylacetat (9*1). Der fås således 1,55 g af den forventede forbindelse, cc-q = +52° +2,5° (c = 0,5$, chloroform). 1Working as in Example 84 from 2.1 g of (IR, cis, ΔΖ) -2,2-dime thyl -3- (3-oxo-3-hydroxy-1-propenyl) -cyclo-propane carboxylic acid ( RS) -cyan-2- (6-phenoxypyridyl) methyl ester prepared as indicated in step D of Example 84 and 1 ml of n-butanol gives an oil which is chromatographed on silica gel eluting with n-hexane and ethyl acetate (9 * 1). Thus 1.55 g of the expected compound is obtained, cc-q = + 52 ° + 2.5 ° (c = 0.5 $, chloroform). 1
Eksempel 88.Example 88.
(IR. cis. ΔΖ) -2.2-d ime th.vl-3- (5-oxo-5-allyloxy-l-propen.vl) --cyclopropancarbox.ylsyre-(RS )-e,van-2-( 6-phenoxypyridyl)-me-thylester.(IR. Cis. ΔΖ) -2,2-dimethyl-3- (5-oxo-5-allyloxy-1-propenyl) -cyclopropanecarboxylic acid (RS) -e, 2- ( 6-phenoxypyridyl) -Me-dimethylester.
Idet man arbejder som i eksempel 84 ud fra 2,1 g (IR,Working as in Example 84 from 2.1 g (IR,
DK 163918BDK 163918B
42 cis,ΔΖ)-2,2-aimethyl-3-(3-oxo-3-hydroxy-l-propenyl)-cyclo-propancarboxylsyre-( RS )-cyan-2-(6-phenoxypyridyl)-me thy lester fremstillet som angivet i trin D i eksempel 84 og 0,8 ml ally lalkohol, får man en olie, som man chromatograferer på si-5 licagel under eluering med n-hexan og ethylacetat (85*15).42 cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-3-hydroxy-1-propenyl) -cyclo-propane carboxylic acid (RS) -cyan-2- (6-phenoxypyridyl) -methyl ester prepared as indicated in step D of Example 84 and 0.8 ml of allyl alcohol, an oil is obtained which is chromatographed on silica gel eluting with n-hexane and ethyl acetate (85 * 15).
Der fås således 1,55 g af den forventede forbindelse, = +53° +3° (c = 0,3$, chloroform).Thus 1.55 g of the expected compound is obtained, = + 53 ° + 3 ° (c = 0.3 $, chloroform).
Eksempel 89.Example 89
10 (IR. cis.ÅZ)-2.2-dimethyl-3-(3-oxo-3-(l.l-dimethylpropoxy)- -propenyl)-cyclopropancarboxylsyre-3-phenoxyphenylmethy lester. Trin A: (IR.cis «ΔΖ)-2. 2-dimethyl-3-(3-oxo-3-(1.1-d imethylprop-oxy)-propynyl)-cyclopropancarboxylsyre-3-Phenoxyphe-nylméthylester.(IR, cis.ÅZ) -2,2-dimethyl-3- (3-oxo-3- (1,1-dimethylpropoxy) -propenyl) -cyclopropane carboxylic acid 3-phenoxyphenylmethyl ester. Step A: (IR.cis «ΔΖ) -2. 2-dimethyl-3- (3-oxo-3- (1,1-dimethylpropoxy) propynyl) cyclopropane carboxylic acid 3-Phenoxyphenylmethyl ester.
15 lian blander 3 g af den i trin B i eksempel 83 fremstil lede forbindelse, 3 ml methylenchlorid, 1 ml tert.-amylalkohol og 0,1 g dimethylaninopyridin. ilan tilsætter under omrøring og ved 5°C 1,75 g dicyolohexylcarbodiimid i 1 ml methylenchlorid, lader genantage stuetemperatur og omrører i 4 ti-20 mer 30 minutter, lian filtrerer, inddamper filtratet til tørhed under formindsket tryk og chromatograferer resten på sili-cagel under eluering med hexan og ethylacetat (S:2), Der fås 1,05 g af den forventede forbindelse.15 ml mix 3 g of the compound prepared in step B of Example 83, 3 ml of methylene chloride, 1 ml of tert-amyl alcohol and 0.1 g of dimethylaninopyridine. In stirring and at 5 ° C, ilan adds 1.75 g of dicyolohexylcarbodiimide in 1 ml of methylene chloride, recharge at room temperature and stir for 4 to 30 minutes, filter, evaporate the filtrate to dryness under reduced pressure and chromatograph the residue on silica gel. eluting with hexane and ethyl acetate (S: 2), 1.05 g of the expected compound are obtained.
Trin 3: (lR.cis.åZ)-2.2-6imethyl-3-(3-oxo-3-(l,l-dimeth.yl-25 propoxy)-propenyl)-cyclopropane arboxyIsyre-3-phenoxy- phenylaethylester.Step 3: (1R.cis.AZ) -2.2-6imethyl-3- (3-oxo-3- (1,1-dimethyl-propoxy) -propenyl) -cyclopropane-arboxylic acid-3-phenoxy-phenyl-ethyl ester.
Man foretager en hydrogenering af 1,05 g af den i forrige trin fremstillede forbindelse i 20 ml ethylacetat i nærværelse af 0,2 g palladiumhydroxid (10$ på bariumsulfat) og 30 0,2 ml quinolin. Man filtrerer, vasker filtratet med 0,1 IHydrogenation of 1.05 g of the compound of the previous step is carried out in 20 ml of ethyl acetate in the presence of 0.2 g of palladium hydroxide ($ 10 on barium sulfate) and 0.2 ml of quinoline. Filter, wash the filtrate with 0.1 L
saltsyre og derefter med vand, tørrer det og inddamper det til tørhed under formindsket tryk, chromatograferer resten på silieagel under eluering med hexan og ethylacetat (95*5) og får 0,756 g af den forventede forbindelse, = +56,5° 35 +2,5° (c = 1$, chloroform).hydrochloric acid and then with water, dry it and evaporate to dryness under reduced pressure, chromatograph the residue on silica gel eluting with hexane and ethyl acetate (95 * 5) to obtain 0.756 g of the expected compound, = + 56.5 ° 35 + 2 , 5 ° (c = 1 $, chloroform).
4343
UIS. ΙΟ^ΰ ΙΟ DUIS. ΙΟ ^ ΰ ΙΟ D
Prsparation 1« (IR« cis , Δ2) -2«2-dimethy 1-5-( 3- ae thoxy-3-oxo-l-propenyl )--Cyclopropancarboxylsyre ,Preparation 1 «(IR« cis, Δ2) -2 »2-Dimethyl 1-5- (3- ae thoxy-3-oxo-1-propenyl) - Cyclopropane carboxylic acid,
Prin A: (IH, cis )-2,2-dimethyl-5-( 5-methoxy-5-oxo-l-propynyl)-5 -cyclopropancarboxylsyre-tert.-butylester.Step A: (1H, cis) -2,2-dimethyl-5- (5-methoxy-5-oxo-1-propynyl) -5-cyclopropane carboxylic acid tert.-butyl ester.
Lian indfører 55 g (lH,cis)-2,2-dimethyl-3-(2,2-di-bromvinyl)-cyclopropancarboxylsyre-tert. -buty les ter i 550 ml tetrahydrofuran. Uan afkøler til -70°C og tilsætter i løbet af 40 minutter 132 ml af en opløsning af butyllithium i cy-10 clohexan (20%) og omrører 30 minutter ved -65°C, Derpå tilsætter man 12,5 ml methylchlorformiat. Efter 2 timers reaktion ved -70°C lader man temperaturen stige til -20°C og hælder den opnåede reaktionsblanding i en vandig mononatrium-phosphatopløsning og ekstraherer med ether. Man vasker, tør-15 rer og inddamper til tørhed undef :foimindsket tryk« Der fås således 38,3 g af en forbindelse, som man chromatograferer på silicagel under eluering med cyclohexan og ethylacetat (8:2), Der fås således 17,2 g af den forventede forbindelse. Trin 3: (1P« cis, ΔΖ )-2.2-dimethyl-5-(3-methoxy-3-oxo-l-prope-20 nyp-cyclopropancarboxylsyre-tert.-butylester.Lian introduces 55 g (1H, cis) -2,2-dimethyl-3- (2,2-di-bromovinyl) cyclopropane carboxylic acid tert. -buty reads in 550 ml of tetrahydrofuran. The uranium cools to -70 ° C and, in 40 minutes, adds 132 ml of a solution of butyllithium in cyclohexane (20%) and stirs for 30 minutes at -65 ° C, then 12.5 ml of methyl chloroformate is added. After 2 hours reaction at -70 ° C, the temperature is allowed to rise to -20 ° C and the reaction mixture obtained is poured into an aqueous monosodium phosphate solution and extracted with ether. Wash, dry and evaporate to dryness under reduced pressure. Thus, 38.3 g of a compound are obtained which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (8: 2) to give 17.2 g of the expected compound. Step 3: (1P, cis, ΔΖ) -2,2-Dimethyl-5- (3-methoxy-3-oxo-1-propane-nip-cyclopropanecarboxylic acid tert-butyl ester.
Man udfører en hydrogenering af 12 g af den i trin A fremstillede forbindelse i 240 ml ethylacetat i nærværelse af 2,4 g palladiumhydroxid (10$ på bariumsulfat) og 2,4 ml qui-nolin. Man filtrerer og tørrer. Der fås således 11 g af den 25 forventede forbindelse.Hydrogenation of 12 g of the compound of step A is performed in 240 ml of ethyl acetate in the presence of 2.4 g of palladium hydroxide ($ 10 on barium sulfate) and 2.4 ml of quinoline. Filter and dry. Thus, 11 g of the 25 expected compound are obtained.
Trin C; (IR,cis«ΔΖ)-2,2-dimethyl-3-(5-methox.v-5-oxo-l-prope-iff!)~cyclopropancarboxylsyre.Step C; (IR, cis "ΔΖ) -2,2-dimethyl-3- (5-methox.v-5-oxo-l-propenyl-IFF) ~ cyclopropane carboxylic acid.
Man tilbagesvaler i 3 timer en opløsning indeholdende 13,5 g af den i trin B fremstillede forbindelse, 100 ml 30 toluen og 400 mg hydratiseret p-toluensulfonsyre. Man inddamper til tørhed under formindsket tryk og får 11,2 g af en forbindelse, som man chromatograferer på silicagel under eluering med cyclohexan, ethylacetat og eddikesyre (60:39si). Man inddamper til tørhed under formindsket tryk og får 9*6 g af den 35 forventede forbindekse med smp. 110°0, = +75,5° +2° (c = 1%, chci5).A solution was refluxed for 3 hours containing 13.5 g of the compound prepared in Step B, 100 ml of toluene and 400 mg of hydrated p-toluenesulfonic acid. Evaporate to dryness under reduced pressure to give 11.2 g of a compound which is chromatographed on silica gel eluting with cyclohexane, ethyl acetate and acetic acid (60: 39si). Evaporate to dryness under reduced pressure to obtain 9 * 6 g of the 35 expected bond index with m.p. 110 ° 0, = + 75.5 ° + 2 ° (c = 1%, chCl 5).
DK 163918 BDK 163918 B
4444
If . Μ. R., CDCIU, ppm: 1,3 : protoner i methylgrupperne i 2-stil- lingen i cyclopropan, 1,86-2 i proton i 1-stillingen i cyclopropan, 3,1 - 3,28 - 3,43 : proton i 3-stillingen i cyclopropan, 5 5,8-5,99 i ethylenisk proton i α-stilling i for hold til gruppen COgCH^, 6,42 - 6,58 j : ethylenisk proton i β-stilling i for- 6,61-6,77 5 i hold til gruppen CC^CH^ 8,63 : proton i gruppen COgH, 10 3,71 : protoner i methoxy«If. Μ. R., CDCIU, ppm: 1.3: protons in the methyl groups in the 2-position in cyclopropane, 1.86-2 in protons in the 1-position in cyclopropane, 3.1 - 3.28 - 3.43: proton at the 3-position in cyclopropane, 5 5.8-5.99 in ethylenic proton in α-position relative to the group COgCH ^, 6.42 - 6.58 j: ethylenic proton in β-position in -6, 61-6.77 5 in the group for the group CC ^ CH ^ 8.63: proton in the group COgH, 10 3.71: protons in methoxy «
Prsparation 2, (1E,c is,ΔΖ)-2,2-d ime thy1-3-(3-8 thoxy-3-oxo-l-propenyl)-cyclo-propancarboxylsyre· 15 Prin Ai (15.cis)-2.2-dimethvl-3-(3-hydroxy-5-oxo-l-propynyl)--syclopropancarboxylsyre-tert.-butylester.Preparation 2, (1E, c is, ΔΖ) -2,2-dimethyl-3- (3-8 thoxy-3-oxo-1-propenyl) -cyclopropanecarboxylic acid · Prin Ai (15.cis) - 2,2-dimethyl-3- (3-hydroxy-5-oxo-l-propynyl) - syclopropancarboxylsyre tert-butyl ester.
Man indfører 26 g (IH,ois)-2,2-dimethy1-3-(2,2-dibrom-vinyl)-cyclopropancarboxylsyre-tert.-butylester i 175 ml vand-frit tetrahydrofuran, Man tilsætter derpå ved -65°C 60 ml 20 20$fs opløsning af butyllithium i cyclohexan. Man omrører 1 time ved -60°0 og lader derpå en strøm af carbondioxid boble igennem i 1 time 30 minutter og hælder reaktionsblandingen i iskoldt vand tilsat 1 If natriumhydroxid opløsning. Man vasker med ether. Den vandige alkaliske fase symes til en pH-værdi 25 på 4 og ekstraheres med ether. Man tørrer de organiske faser og inddamper til tørhed under formindsket tryk. Der fås så4 ledes en forbindelse, som man omkrystalliserer af petroleums-etner (kp 60-80°0). Der fås da 8,3 g af den forventede forbindelse med smp. 144°0.26 g of (1H, ois) -2,2-dimethyl-3- (2,2-dibromo-vinyl) -cyclopropanecarboxylic acid tert-butyl ester are introduced into 175 ml of anhydrous tetrahydrofuran, then added at -65 ° C 60 ml 20 20 $ fs solution of butyllithium in cyclohexane. The mixture is stirred for 1 hour at -60 ° 0 and a stream of carbon dioxide is bubbled for 1 hour 30 minutes and the reaction mixture is poured into ice-cold water added with 1 µl sodium hydroxide solution. Wash with ether. The aqueous alkaline phase is simulated to a pH of 4 and extracted with ether. The organic phases are dried and evaporated to dryness under reduced pressure. A compound is then obtained which is recrystallized from petroleum ether (bp 60-80 ° 0). 8.3 g of the expected compound are obtained with m.p. 144 ° 0th
30 CDCl^, ppm: 1,22 og 1,37 m· protoner i methylgrupperne i 2-stillingen i cyclopropan, 1,78 : proton i 1- og 3-stillingen i cyclopropan, 1.47 : protoner i tert.-butyl,, Ppm: 1.22 and 1.37 m · protons in the methyl groups at the 2-position in cyclopropane, 1.78: protons at the 1 and 3-position in cyclopropane, 1.47: protons in tert-butyl,
35 8,25 : proton i gruppen -C-0E8.25: proton in the -C-OE group
ir o 45 DK itttsnts bir o 45 DK itttsnts b
Trin B: (lR.cis)-2.2-dimethyl-3-(3-ethox.v-3-oxo-l-propynyl)--oyclopropancarboxylsyre-tert.-butylester.Step B: (1R.cis) -2,2-dimethyl-3- (3-ethoxyl-3-oxo-1-propynyl) oyclopropane carboxylic acid tert.-butyl ester.
Man indfører 4 g af den i trin A fremstillede forbindelse, 3,4 g dicyclohexylcarbodiimid og 6 mg 4-dimethylamino-5 pyridin i 30 ml methylenchlorid, Derpå tilsætter man 1,5 ml ethanol og omrører 16 timer ved 20°0. Uian filtrerer og inddamper filtratet under formindsket tryk. Der fås således 5,5 g af en forbindelse, som man renser ved chromatografi på silicagel under eluering med cyelohexan og ethylacetat (9:1)# 10 Der fås således 4,25 g af den forventede forbindelse.4 g of the compound prepared in step A, 3.4 g of dicyclohexylcarbodiimide and 6 mg of 4-dimethylamino-pyridine in 30 ml of methylene chloride are added, then 1.5 ml of ethanol is added and stirred for 16 hours at 20 ° 0. Uian filters and evaporates the filtrate under reduced pressure. There is thus obtained 5.5 g of a compound which is purified by chromatography on silica gel eluting with cyelohexane and ethyl acetate (9: 1) # 10 4.25 g of the expected compound are thus obtained.
U.M.R,, CDCl^, ppm: 1,18 - 1,21 og 1,36 - 1,47: protoner i 2-stillingen i cyclo- propan, 1,73 og 1,82 : protoner i 1- og 3-stillingen i 15 cyclopropan, 1,47 : protoner i tert.-butyl, 1»27 - 1,38 - 1,5 u protoner i ethyl.UMR, CDCl3, ppm: 1.18 - 1.21 and 1.36 - 1.47: protons at the 2-position in cyclopropane, 1.73 and 1.82: protons at the 1 and 3 positions in cyclopropane, 1.47: protons in tert-butyl, 1 »27 - 1.38 - 1.5 u protons in ethyl.
4,0 - 4,13 - 4,25 - 4,36)4.0 - 4.13 - 4.25 - 4.36)
Trin C: (iR.cis.åZ)-2.2-dimethyl-3-(3-ethoxy-5-oxo-l-prope-20 n.vl)-cyclopropancarboxylsyre-tert.-butylester.Step C: (iR.cis.AZ) -2,2-dimethyl-3- (3-ethoxy-5-oxo-1-prope-20-nyl) -cyclopropane carboxylic acid tert-butyl ester.
Man foretager en hydrogenering af 4,3 g af det i forrige trin fremstillede stof i 100 ml ethylacetat i nærværelse af 800 mg palladiumhydroxid på bariumsulfat og 0,8 ml quinolin. Man filtrerer, bringer filtratet på en pH-værdi un-25 der 7 med 2 3? saltsyre og vasker med vand. Man tørrer og inddamper til tørhed under formindsket tryk. Der fås 4,6 g af en forbindelse, som man chromatograferer på silicagel under eluering med cyelohexan og ethylacetat (95:5). Der fås således 2,5 g af den forventede forbindelse:*.Hydrogenation of 4.3 g of the substance prepared in the previous step is carried out in 100 ml of ethyl acetate in the presence of 800 mg of palladium hydroxide on barium sulfate and 0.8 ml of quinoline. Filtering, brings the filtrate to a pH below 7 with 2 3? hydrochloric acid and wash with water. Dry and evaporate to dryness under reduced pressure. 4.6 g of a compound are obtained which are chromatographed on silica gel eluting with cyelohexane and ethyl acetate (95: 5). Thus, 2.5 g of the expected compound are obtained:.
30 N.M.R., ODCLj, ppm: 1,25 og 1,28 : protoner i methylgrupperne i 2-stillingen i cyclopropan, 1,78 - 1,93 : proton i 1-stillingen i cyclopropan, 2,98-3,1 -5,2 : proton i 3-stillingen i cyclopropan, 35 6,4 - 6,6 - 6,8 : proton v. ethylenisk carbon i oc- -stilling i forhold til cyclopropan,NMR, ODCL₂, ppm: 1.25 and 1.28: protons in the methyl groups at the 2-position in cyclopropane, 1.78 - 1.93: proton at the 1-position in cyclopropane, 2.98-3.1 -5 , 2: proton at the 3-position in cyclopropane, 6.4 - 6.6 - 6.8: proton v. Ethylenic carbon in the o-position relative to cyclopropane,
DK 163918BDK 163918B
46 5,7 - 5>9 : proton ved ethylenisk cartonatom, som bærer ethoxycarbonylgruppen, 4,0 - 4,15 - 4,25 - 4,36 : proton i methylengruppen 1 ethoxy. Trin D; (IR.cis.ΔΖ)-2.2-dimethy1-5-(5-ethoxy-5-oxo-1-propenyl)-5 -cyolopropanoarboxylsyre.46 5.7 - 5> 9: proton at ethylenic carton atom bearing the ethoxycarbonyl group, 4.0 - 4.15 - 4.25 - 4.36: proton in the methylene group 1 ethoxy. Step D; (IR.cis.ΔΖ) -2,2-dimethyl-5- (5-ethoxy-5-oxo-1-propenyl) -5-cyolopropanoarboxylic acid.
Han indfører 2,5 g af den i trin C fremstillede forbindelse og 20 mg hydratiseret p-toluensulfonsyre i 20 ml toluen. Lian opvarmer til tilbagesvaling i 40 minutter, inddamper til tørhed uncer .formindsket tryk og får således 2,1 g af en rest, 10 som man chromatograferer på silicagel under eluering med cyclo-hexan, ethylaoetat og eddikesyre (60:39:1). Han isolerer 1,7 g forbindelse, som man omkrystalliserer af cyclohexan. Der fås således 1,5 g af den forventede forbindelse med smp. 96°C.He introduces 2.5 g of the compound prepared in step C and 20 mg of hydrated p-toluenesulfonic acid in 20 ml of toluene. Lian heats to reflux for 40 minutes, evaporates to dryness under reduced pressure, and thus obtains 2.1 g of a residue which is chromatographed on silica gel eluting with cyclohexane, ethyl acetate and acetic acid (60: 39: 1). He isolates 1.7 g of compound which is recrystallized from cyclohexane. Thus 1.5 g of the expected compound are obtained with m.p. 96 ° C.
Ϊ!.M. R., CD Cl^, ppm: 15 1,3 og 1,32 : protoner i methylgruppeme i 2-stillingen i cyclopropan, 1,86 - 2,02 : proton ved carbonatomet i 1-stillingen i cyclopropan, 3,15-3,28 I . proton ved carbonatomet i 3-stillingen i 20 3,3 - 3,45 ) cyclopropan 6,38-6,53 ) .proton ved det ethyleniske carbonatom 6,55 - 6*,73 } : forgrenet på cyclopropan, 5,78-5,96 : proton ved det ethyleniske carbonatom, som bærer ethoxycarbonylgruppen, 25 1,18 - 1,3 - 1,41 : protoner i methylgruppen i ethoxycarbo nylgruppen, 4,0-4,13 j . protoner i methylgruppen i ethoxycar- 4,25-4,36 ) bonylgruppen, 30 Præparation 5.Ϊ! .M. R, CD Cl 2, ppm: 1.3 and 1.32: protons in the methyl groups at the 2-position in cyclopropane, 1.86 - 2.02: proton at the carbon atom at the 1-position in cyclopropane, 3.15 3.28 I. proton at the carbon atom at the 3-position of 3.3 - 3.45) cyclopropane 6.38-6.53) proton at the ethylenic carbon atom 6.55-6 *, 73}: branched on cyclopropane, 5.78- 5.96: proton at the ethylenic carbon atom bearing the ethoxycarbonyl group, 1.18 - 1.3 - 1.41: protons in the methyl group of the ethoxycarbonyl group, 4.0-4.13 j. protons in the methyl group of the ethoxycar- 4,25-4,36) bonyl group, Preparation 5.
(1P„ cis. ΔΖ) -2.2-dime th.vl-5-( 5-propoxo-5-oxo-l-propenyl) -oy-clopropancarboxylsyre.(1β-cis. ΔΖ) -2,2-dime thyl-5- (5-propoxo-5-oxo-1-propenyl) -ylo-propanecarboxylic acid.
Trin A: (1 R.cis)-2.2-dimethyl-5-propoxy-5-oxo-l-propynyl-cyclopropane arb ox y1s yre-tert.-butyles t er.Step A: (1R.cis) -2,2-dimethyl-5-propoxy-5-oxo-1-propynyl-cyclopropane arboxyl acid tert.-butyls.
35 Lian indfører 22,8 g (lR,cis)-2,2-dimethyl-3*-(2,2-di- bromvinvl)-cyclopropancarboxylsyre-tert.-butylester og 250 ml tetrahydrofuran og derefter ved -60°C 55 ml 20$’s butyllithium- . 47 υκ itjjyio d opløsning i cyclohexan. Han holder ved -65°C i 1 time og indfører ved -65°C i løbet af 15 minutter S ml n-propylchlor-formiat. Han fortsætter omrøringen i 1 time ved -65°C, lader temperaturen stige til stuetemperatur i løbet af 1 time og 5 omrører atter 1 time ved stuetemperatur. Lian hælder på en mættet vandig mononatrium phosphatcpløsning, omrører, ekstrahe-rer med ether og vasker med vand. Lian tørrer og inddamper til tørhed under formindsket tryk. Ter fås således 19,5 g af en olie, som man renser ved ehromatografi på silicagel under elue-10 ring med cyclohexan og ethylacetat (3*1)# Ter fås såsledes 11,5 g af den forventede forbindelse, , CTC1X, ppm: 1,17 og 1,37 * protoner i methylgrupperne i 2-stillin- gen i cyclopropan, 15 1,72 : protoner i 1- og 3-stillingen i cyclo propan, 1,44 : protoner i tert,-butyl, 4,0-4,12-4,23 : proton i methylengruppen i 1-stillingen i propoxycarbonyl, 20 0,83 - 0,95 - 1,06 ; protoner i methylgruppen i propoxycar bonyl.Lian introduces 22.8 g (1R, cis) -2,2-dimethyl-3 * - (2,2-dibromovinyl) -cyclopropane carboxylic acid tert.-butyl ester and 250 ml of tetrahydrofuran and then at -60 ° C 55 ml of 20 $ butyllithium. 47 υκ itjjyio d solution in cyclohexane. He maintains at -65 ° C for 1 hour and introduces at -65 ° C over 15 minutes S ml of n-propyl chloro formate. He continues stirring for 1 hour at -65 ° C, allowing the temperature to rise to room temperature over 1 hour and again stirring for 1 hour at room temperature. Lian pours on a saturated aqueous monosodium phosphate solution, stirring, extracting with ether and washing with water. Lian dries and evaporates to dryness under reduced pressure. Teres are thus obtained 19.5 g of an oil which is purified by ehromatography on silica gel eluting with cyclohexane and ethyl acetate (3 * 1). # Ter is thus obtained 11.5 g of the expected compound, CTC1X, ppm: 1.17 and 1.37 * protons in the methyl groups at the 2-position in cyclopropane, 1.72: protons at the 1- and 3-position in cyclo propane, 1.44: protons in tert, -butyl, 4, 0-4.12-4.23: proton in the methylene group at the 1-position in propoxycarbonyl, 0.83 - 0.95 - 1.06; protons in the methyl group of propoxycar bonyl.
Trin 5: (IR,ois,ΔΖ )-2,2-dimeth.vi-5-(3-propoxy-3~ox:o~l-pro-penvl) -cyclopropancarboxylsyre-tert, -but.y lester.Step 5: (IR, ois, ΔΖ) -2,2-dimethyl-5- (3-propoxy-3-ox: o-1-propenyl) -cyclopropane carboxylic acid tert -butyl ester.
Han hydrogenerer 7 g (lH,cis)-2,2-dimethyl-3-(n-prop-25 oxy-3-oxo-l-propynyl)-cyclopropancarboxylsyre-tert,-butyl-ester i 140 ml ethylacetat i nærværelse af 1,4 g palladiumhydroxid (10fo på bariumsulfat) og 1,4 ml quinolin. Han vasker filtratet med 2 Ή saltsyre og vasker derefter med vand, tørrer og inddamper til tørhed under formindsket tryk. Ter 30 fås således 7,2 g af en forbindelse, som man chromatograferer på silicagel under eluering med cyclohexan og ethylacetat (95*5). Lian får således 6,1 g af den forventede forbindelse. Hi.LI.R., CTCl^, ppm: 1,25 og 1,29 : proton i methylgrupperne i 2-stillingen 35 i cyclopropan, 1,5 til 2,03 * proton ved carbonatomet i 1-stillingen i cyclopropan,He hydrogenates 7 g (1H, cis) -2,2-dimethyl-3- (n-prop-oxy-3-oxo-1-propynyl) -cyclopropanecarboxylic acid tert -butyl ester in 140 ml of ethyl acetate in the presence of 1.4 g of palladium hydroxide (10 µl on barium sulfate) and 1.4 ml of quinoline. He wash the filtrate with 2 Ή hydrochloric acid and then wash with water, dry and evaporate to dryness under reduced pressure. Thus, ter 30 is obtained 7.2 g of a compound which is chromatographed on silica gel eluting with cyclohexane and ethyl acetate (95 * 5). Thus, Lian gets 6.1 g of the expected compound. Hi.LI.R., CTCl 2, ppm: 1.25 and 1.29: proton in the methyl groups at 2-position 35 in cyclopropane, 1.5 to 2.03 * proton at the carbon atom at 1-position in cyclopropane,
DK 163918 BDK 163918 B
48 5 05 til 5,35 : proton, ved ca::bonatomet i 3-stillingen i oyclopropan, 6,5-6,66 | s proton ved det ethyleniske carbonaton, 6,69-6,85 ) : som er forbundet med oyclopropan, 5 5,82-6,0 : proton ved det ethyleniske carbonatom, som bærer propoxycarbonylgruppen, 4,02-4,12-4,23 : proton i methylengruppen i 1-stillingen i propoxycarbonylgruppen, 0,86 - 0,98 - 1,1 : proton ved methylgruppen i propoxycarlo bonylgruppen, grin 0: (IR« cis .ΔΖ )-2.2-dimethy 1-5-( 5-propoxy-3-oxo-l-prope-nvl )-cyclopropancarboxyls.yre.48 5 05 to 5.35: proton, at about :: the bon atom at the 3-position of oyclopropane, 6.5-6.66 | s proton at the ethylenic carbonatone, 6.69-6.85): associated with oyclopropane, 5.82-6.0: proton at the ethylenic carbon atom bearing the propoxycarbonyl group, 4.02-4.12-4 , 23: proton in the methylene group at the 1-position in the propoxycarbonyl group, 0.86 - 0.98 - 1.1: proton in the methyl group in the propoxycarbonyl group, laugh 0: (IR «cis .ΔΖ) -2,2-dimethyl 1-5- (5-propoxy-3-oxo-1-prope-nyl) -cyclopropane carboxylic acid.
Han tilbagesvaler i 1 time en blanding af 5,8 g af det i trin 3 fremstillede stof, 200 mg hydratiseret p-toluen-15 sulfonsyre og 60 ml toluen· Lian inddamper til tørhed under formindsket tryk og får 5 g af en forbindelse, som man chroma-tograferer på silicagel under eluering med cyclohexan, ethyl-acetat og eddikesyre (70:29:1). Der fås 4,2 g af den forventede forbindelse.He refluxes for 1 hour a mixture of 5.8 g of the substance prepared in step 3, 200 mg of hydrated p-toluene-15 sulfonic acid and 60 ml of toluene · Lian evaporates to dryness under reduced pressure to obtain 5 g of a compound which chromatography on silica gel eluting with cyclohexane, ethyl acetate and acetic acid (70: 29: 1). 4.2 g of the expected compound are obtained.
20 CDCl^, ppm: 1,27 og 1,29 : H i methylgrupperae i 2-stillingen i oyclopropan, 1,86-2 : H i 1-stillingen i oyclopropan, 5,15 til 5,45 : H i 3-stillingen i oyclopropan, 25 5,8-6 : H ved det ethyleniske carbonatom, som bærer gruppen CO2CHgCE^CH^, 6,4 - 6,56 - 6,59 '· Η ved det ethyleniske carbonatom, som er bundet til oyclopropan, 3,98 - 4,08 - 4,18 : Hi methylengruppen i 1-stillingen i 30 propoxycarbonylgruppen, 0,83 - 0,95 - 1,06 s H i methylgrupperne i propoxycarbonylgruppen.CDCl3, ppm: 1.27 and 1.29: H in methyl grouperae at the 2-position in oyclopropane, 1.86-2: H at the 1-position in oyclopropane, 5.15 to 5.45: H in 3- the position in oyclopropane, 5.8-6: H at the ethylenic carbon atom bearing the group CO2CHgCE2CH2, 6.4 - 6.56 - 6.59 '· Η at the ethylenic carbon atom attached to oyclopropane, 3.98 - 4.08 - 4.18: The H 1 methylene group at the 1-position in the propoxycarbonyl group, 0.83 - 0.95 - 1.06 s H in the methyl groups in the propoxycarbonyl group.
35 49 DK 163318 b35 49 DK 163318 b
Præparation 4.Preparation 4.
(IR, cis, ΔΖ )-212-dimethyl-3-( 5-( 1-methylethoxy )-3-oxo-l-prope -nyl)-cyclopropancarboxylsyre.(IR, cis, ΔΖ) -212-dimethyl-3- (5- (1-methylethoxy) -3-oxo-1-prope-nyl) -cyclopropane carboxylic acid.
grin A: (1R. c i s. ΔΖ) -2,2 -d ime th y 1 -3 - (5 -h yd r oxy -3 -ox o -1 -pr o pe -5 ‘ n.yl)-oyclopropancarboxyls.vre-tert «-but,vies ter.Grin A: (1R. ci s. ΔΖ) -2,2 -d ime th y 1 -3 - (5 -hydroxy-3-oxo-1-pr o pe -5 'n.yl) - oyclopropane carboxyls.vre-tert «-but, dirty ter.
Lian hydrogenerer 2 g (lR,cis)-2,2-dimethyl-3-(3-hy-droxy-3-oxo-l~propynyl)-cyclopropancs.rboxylsyre -tert.-butyl-ester i 40 ml ethylacetat i nærværelse af 0,38 g palladiumhydroxid (105¾ på bariumsulfat) og 0,4 ml quinolin. Lian filtre-10 rer, vasker filtratet med 0,5 H- saltsyre og derefter med vand indtil neutralitet, tørrer, inddamper til tørhed under formindsket tryk og får 2 g af den forventede forbindelse med smp. 94°C.Lian hydrogenates 2 g (1R, cis) -2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propynyl) -cyclopropanic acid-tert-butyl ester in 40 ml of ethyl acetate in the presence of 0.38 g of palladium hydroxide (105¾ on barium sulfate) and 0.4 ml of quinoline. Lian filters, the filtrate was washed with 0.5 H hydrochloric acid and then with water until neutrality, dried, evaporated to dryness under reduced pressure and obtained 2 g of the expected compound, m.p. 94 ° C.
grin B; (IR, ois «ΔΖ)-2.2-dimethyl-3-(3-(1-methylethoxy)-5-oxo-15 -l-propen.vl)-cyclopropancarboxyls.vre-tert.-butylester.grin B; (IR, αisΖ) -2,2-dimethyl-3- (3- (1-methylethoxy) -5-oxo-15-1-propenyl) cyclopropane carboxylic acid tert-butyl ester.
lian blander 2,7 g (lR,cis)-2,2-dimethyl-3-((Z)-3-hy-droxy-3-oxo-1-propenyl)-cyclopropancarboxylsyre-tert,-butyl-ester i 10 ml ethylacetat, tilsætter derpå 2 g 0-isopropyl--!?, II’ -diisopro py lisourinstof og omrører i 1 time ved stuetem-20 peratur. Lian opvarmer til tilbagesvaling i 1 time 30 minutter, lader temperaturen vende tilbage til 20°C, frafiltrerer uopløseligt materiale cg inddamper filtratet til tørhed under formindsket tryk. Per fås 3»5 g af en olie, som man chromato-graferer på silicagel under eluering med benzen og cyclohexan 25 (7:3). Der fås således 1 g af den forventede forbindelse, som man umiddelbart benytter i det følgende trin.lian mixes 2.7 g (1R, cis) -2,2-dimethyl-3 - ((Z) -3-hydroxy-3-oxo-1-propenyl) -cyclopropane carboxylic acid tert, butyl ester in 2 ml of ethyl acetate, then add 2 g of 0-isopropyl-1? II-diisopropylpyric acid and stir for 1 hour at room temperature. Lian heats to reflux for 1 hour 30 minutes, returns to 20 ° C, filters insoluble material and evaporates the filtrate to dryness under reduced pressure. Per 3, 5 g of an oil is obtained which is chromatographed on silica gel eluting with benzene and cyclohexane 25 (7: 3). Thus, 1 g of the expected compound is obtained, which is used immediately in the following step.
Trin C: (IR.cis,ΔΖ)-2,2-dimethy 1-3-(3-( 1-meth.vlethoxy)-3-oxo--1-propenyl )-c.volonropancarboxylsyre.Step C: (IR.cis, ΔΖ) -2,2-dimethyl 1-3- (3- (1-methylethoxy) -3-oxo-1-propenyl) -cvolonropanecarboxylic acid.
Lian opvarmer til 120° under omrøring i 2 timer 30 mi-50 nutter en blanding indeholdende 1,4 g (lE,cis,åZ)-2,2-dime-thyl-3-(3-(1-methylethoxy)-3-oxo-l-propenyl)-cyclopropancarb-oxylsyre-tert.-butylester, 100 mg p-toluensulfonsyre og 14 ml toluen. Lian inddamper til tørhed under formindsket tryk. Per fås en rest, som man omkrystalliserer af isopropylether. lian 35 isafkøler, suger fra, tørrer og får således 500 mg af den forventede forbindelse med smp. 98°G.Lian heats to 120 ° with stirring for 2 hours 30 ml-50 nuts a mixture containing 1.4 g (1E, cis, ÅZ) -2,2-dimethyl-3- (3- (1-methylethoxy) -3 -oxo-1-propenyl) -cyclopropanecarboxylic acid tert-butyl ester, 100 mg of p-toluenesulfonic acid and 14 ml of toluene. Lian evaporates to dryness under reduced pressure. Per is obtained a residue which is recrystallized from isopropyl ether. lian 35 ice-cooler, sucks, dries and thus receives 500 mg of the expected compound with m.p. 98 ° G.
DK 163918BDK 163918B
5050
Præparation 5.Preparation 5.
(l£.cis.AZ)-2.2-dimeth,vl-5-(3-cyolobutyloxy-5-oxo-l-prope- n.vl )-cyclopropancarboxyIsyre.(1β-cis.AZ) -2,2-dimethyl-5- (3-cyolobutyloxy-5-oxo-1-propylene-yl) -cyclopropane carboxylic acid.
grin A: (IR, cis. ΔΖ)-2,2-d imethyl-3-( 3-c.vclobutyloxy-5-oxo-5 -l-propenyl)-cyclopropancarboxyIsyre-tert.-buty lester«lane A: (IR, cis. ΔΖ) -2,2-dimethyl-3- (3-cyclobutyloxy-5-oxo-5-1-propenyl) -cyclopropanecarboxylic acid tert-butyl ester
Lian opløser 4 g (lE,cis,AZ)-2,2-dimethyl-3-(3-hydroxy--3-oxo-l-propenyl)-cyclopropancarbox3MLsyre-tert.-butylester i 20 methylenchlorid og tilsætter derpå 1,7 mg cyelobuta-ncl. Lian sænker temperaturen til nellem 0 og 5°C og tilsætter 10 3,45 g dicyclohexylcarbodiimid og 28 mg dimethylaminopyridin i 20 mg methylenchlorid og fortsætter omrøringen i 2 timer ved ca. 5°C og 2 timer ved stuetemperatur. Lian eliminerer det dannede dicyclohexylurinstof, inddamper filtratet til tørhed og chromatograferer på silicagel under eluering med en blan-15 ding af n-hexan og isopropylether (9il)« Per fås 2,3 g af den forventede forbindelse.Lian dissolves 4 g (1E, cis, AZ) -2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propenyl) -cyclopropane carboxylML-tert.-butyl ester in methylene chloride and then adds 1.7 mg cyelobuta-ncl. Lian lowers the temperature to between 0 and 5 ° C and adds 10 3.45 g of dicyclohexylcarbodiimide and 28 mg of dimethylaminopyridine in 20 mg of methylene chloride and continues stirring for 2 hours at approx. 5 ° C and 2 hours at room temperature. Lian eliminates the dicyclohexylurea formed, evaporates the filtrate to dryness and chromatographs on silica gel eluting with a mixture of n-hexane and isopropyl ether (9il). Per 2.3 g of the expected compound is obtained.
Trin B; (15,ois.ΔΖ)-2«2-dimethyl-3-(3-cyclobutyloxy-3-oxo-l--propenyl )-cyclopropanoarboxylsyre.Step B; (15, ois.ΔΖ) -2'-2-dimethyl-3- (3-cyclobutyloxy-3-oxo-1-propenyl) -cyclopropanoarboxylic acid.
Lian opvarmer til tilbage svaling i 15 minutter 2,3 g 20 af den ovenfor fremstillede forbindelse, 25 ml toluen og 250 mg p-toluensulfonsyre, afkøler og omrører i 2 timer ved en temperatur mellem 0 og 45°C. Man frafiltrerer det uopløselige materiale og inddamper filtratet til tørhed og får 1,8 g af den forventede forbindelse.For 15 minutes, Lian refluxes 2.3 g of 20 of the above compound, 25 ml of toluene and 250 mg of p-toluenesulfonic acid, cools and stirs for 2 hours at a temperature between 0 and 45 ° C. The insoluble material is filtered off and the filtrate is evaporated to dryness to give 1.8 g of the expected compound.
25 I «Β. spektrum: -0Ξ: syre 3500 cm”*1· -0=0: syre 1733 em”1 + ester ca. 1702 cm”1 tvill.-di-Ke 1390 cm”1 30 1380 cm”125 I «Β. spectrum: -0Ξ: acid 3500 cm ”* 1 · -0 = 0: acid 1733 cm” 1 + ester approx. 1702 cm ”1 twin-di-Ke 1390 cm” 1 30 1380 cm ”1
Præparation 6.Preparation 6.
(l£.cis.AZ)-2.2-dimethyl-3-(3-(PS)-l-methylpropyloxy-3-oxo-l- -propsnyl)-cyolopropancarboxylsyre.(1β-cis.AZ) -2,2-dimethyl-3- (3- (PS) -1-methylpropyloxy-3-oxo-1-propsnyl) -cyolopropane carboxylic acid.
35 Trin A: (lE.cis)-2.2-dimethyl-3-(3-(3S)-l-methylpropyloxy-3- -oxo-1-pro pyny1)-c y clopro panoarb oxyIs yre-tert,-buty1-ester.Step A: (1E.cis) -2,2-Dimethyl-3- (3- (3S) -1-methylpropyloxy-3--oxo-1-pro-pynyl) -cyclo-propanoic acid, tert-butyl ester .
Man blander 4 g (IPl, cis )-2,2-dimethy 1-3-( 3-bydroxy-Mix 4 g of (IPI, cis) -2,2-dimethyl 1-3- (3-hydroxy)
L/IV 1009 ΙΟ DL / IV 1009 ΙΟ D
51 -3-oxo-l-p*opynyl)-cyclopropancarboxylsyre-tert.-butylester, 40 ml methylenchlorid og 6 mg 4-dimethylaminopyridin, og derpå tilsætter man 3,4 g dicyclohexylcarbodiimid. Efter 30 minutters omrøring under indifferent atmosfære og i 2 ml methy-5 lenchlorid tilsætter man i løbet af 5 minutter 2 ml 1-methyl-propanol og 2 ml methylenchlorid og fortsætter omrøringen i 3 timer ved stuetemperatur. Man frafiltrerer det dannede dicyclohexylurinstof, inddamper filtratet til tørhed under formindsket tryk og chromatograferer resten på silicagel un-10 der eluering med en blanding af n-hexan og isopropylether (8:2). Der fås 3,5 g af den forventede forbindelse.51 -3-oxo-1-p (opynyl) -cyclopropane carboxylic acid tert.-butyl ester, 40 ml of methylene chloride and 6 mg of 4-dimethylaminopyridine, and then 3.4 g of dicyclohexylcarbodiimide are added. After stirring for 30 minutes under inert atmosphere and in 2 ml of methylene chloride, 2 ml of 1-methylpropanol and 2 ml of methylene chloride are added over 5 minutes and stirring is continued for 3 hours at room temperature. The resulting dicyclohexylurea is filtered off, the filtrate is evaporated to dryness under reduced pressure and the residue is chromatographed on silica gel eluting with a mixture of n-hexane and isopropyl ether (8: 2). 3.5 g of the expected compound are obtained.
Trin B: (IR.cis.ΔΖ )-2.2-dimeth.vl-3-(3-(BS )-l-methylpropyloxy--3-oxo-1-propenvl)-oyclopropancarboxyls y re-te rt. --butylester.Step B: (IR.cis.ΔΖ) -2,2-dimethyl-3- (3- (BS) -1-methylpropyloxy-3-oxo-1-propenyl) oyclopropane carboxylic acid. --butylester.
15 Man hydrogenerer 3 g af den forbindelse, der er frem stillet som angivet ovenfor i præparation 4. Man chromatograferer på silicagel under eluering med en blanding af n-hexan og isopropylether (9:1) og får 2,5 g af den forventede forbindelse.Hydrogenate 3 g of the compound prepared as above in Preparation 4. Chromatograph on silica gel eluting with a mixture of n-hexane and isopropyl ether (9: 1) to give 2.5 g of the expected compound .
20 Jrin C: (lR,cis.AZ)-2«2-dimethyl-3-(3-(RS)-l-methylpropyloxy--3*oxo-l-propenyl)-oyclopropanoarboxyls.vre.Jrin C: (1R, cis.AZ) -2- 2-dimethyl-3- (3- (RS) -1-methylpropyloxy-3 * oxo-1-propenyl) -oyclopropanoarboxylic acid.
Man omrører 3 g af den ovenfor fremstillede forbindelse med 250 mg p-toluensulfonsyre i 25 ml toluen. Man opvarmer til tilbagesvaling indtil ophør af gasudviklingen. Man ind-25 damper til tørhed under formindsket tryk og chromatograferer resten på silicagel under eluering med en blanding af cyclo-hexan, ethylacetat og eddikesyre (70:30:1). Der fås 1,85 g af den forventede forbindelse.3 g of the compound prepared above are stirred with 250 mg of p-toluenesulfonic acid in 25 ml of toluene. Reflux is heated until gas evolution ceases. Evaporate to dryness under reduced pressure and chromatograph the residue on silica gel eluting with a mixture of cyclohexane, ethyl acetate and acetic acid (70: 30: 1). 1.85 g of the expected compound are obtained.
I. R.spektrum (CHOl^): 30 .OH : syre 3510 cm’1 -0=0: syre 1735 em”1 ester 1170 cm”1 kon}. C=C 1637 cm”1 tvill, di-Me 1381 cm’1 35I.R. Spectrum (CHO1): 30 OH: acid 3510 cm -1 = 0: acid 1735 cm -1 ester 1170 cm 1 con}. C = C 1637 cm 1 twin, di-Me 1381 cm -1 35
DK 163918BDK 163918B
5252
Præparation 7· (IR.cis,ΔΖ)-2.2-dimethyl-3-(3-oxo-5-(cyelopropylmethoxy))--propenylovclopropan-l-carboxylsyre.Preparation 7 · (IR.cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-5- (cyclopropylmethoxy)) -propenyloclopropane-1-carboxylic acid.
Trin A: (IR.ois «ΔΖ )-2«2-dimeth.vl-3-(3-oxo-3-oyclopropyl-5 methoxy )-propenylcyclopropan-l-carboxylsyre-tert.- -butylester.Step A: (IR.iso ΔΖ) -2 "2-Dimethyl-3- (3-oxo-3-oyclopropyl-methoxy) -propenylcyclopropane-1-carboxylic acid tert-butyl ester.
I 150 ml methylenchlorid indfører man 20 g (lR,cis,AZ)--2,2-dimethyl-3-(3-hydroxy-3-oxo-l~propenyl)-cyclopropan-l--carboxylsyre-tert.-butylester og 6,2 g eyclopropylearbinol, 10 hvorpå man tilsætter 2 g dimethylaminopyridin og 17,5 g di-eyclohexylcarbodiimid opløst i 60 ml methylenchlorid, og man omrører i 2 timer ved 20°C, eliminerer det dannede uopløselige materiale, inddamper til tørhed ved destillation under formindsket tryk og chromatograferer resten på silicagel un-15 der eluering med en blanding af hexan og isopropylether (9:1)· Rer fås 12,32 g (l£,ei*,AZ)-2,2-dimethyl-5-(3-oxo-3-cyelopro-pylmethoxy)-propenylcyclopropan-l-earboxylsyre-tert,-butylester.Into 150 ml of methylene chloride are introduced 20 g (1R, cis, AZ) - 2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propenyl) cyclopropane-1-carboxylic acid tert-butyl ester and 6.2 g of eyclopropylearbinol, adding 2 g of dimethylaminopyridine and 17.5 g of di-cyclohexylcarbodiimide dissolved in 60 ml of methylene chloride and stirring for 2 hours at 20 ° C, eliminating the insoluble material formed, evaporating to dryness by distillation. under reduced pressure and chromatograph the residue on silica gel eluting with a mixture of hexane and isopropyl ether (9: 1) · Rer is obtained 12.32 g (l, e, * AZ) -2,2-dimethyl-5- (3-oxo-3-cyelopro-pylmethoxy) -propenylcyclopropan earboxylsyre-l-tert-butyl ester.
Trin B: (IR.cis.ΔΖ)-2.2-dimethyl-5-(5-oxo-3-cyclopropylmeth-20 oxy)-propenylcyclopropan-l-carboxylsyre.Step B: (IR.cis.ΔΖ) -2,2-dimethyl-5- (5-oxo-3-cyclopropylmethoxy) propenylcyclopropane-1-carboxylic acid.
I 120 ml toluen indfører man 12,32 g (lR,cis,AZ)-2,2--dimethyl-3-(3-oxo-3-cyclopropylmethoxy)-propenylcycloprop an--1-carboxylsyre-tert.-butylester og 0,6 g p-toluensulfonsyre, og man opvarmer til tilbagesvaling, opretholder tilbagesva-25 lingen i 45 minutter, afkøler, inddamper til tørhed ved destillation under formindsket tryk, chromatograferer resten på silicagel under eluering med en blanding af hexan og ethylacetat (7:3) tilsat 1# eddikesyre og får 8,94 g (IR,cis, ΔΖ )-2,2-dimethyl-3-(3-oxo-3-cyelopropylmethoxy )-propenyley-30 clopropan-l-carboxylsyre med smp. 106°C.Into 120 ml of toluene are added 12.32 g (1R, cis, AZ) -2,2-dimethyl-3- (3-oxo-3-cyclopropylmethoxy) propenylcyclopropane - 1-carboxylic acid tert-butyl ester and 0.6 g of p-toluenesulfonic acid and heated to reflux, the reflux maintained for 45 minutes, cooled, evaporated to dryness under reduced pressure, chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (7: 3) added 1 # acetic acid to give 8.94 g (IR, cis, ΔΖ) -2,2-dimethyl-3- (3-oxo-3-cyclopropylmethoxy) propenyley-clopropane-1-carboxylic acid, m.p. 106 ° C.
R.M.R., 0DC1^, ppm: 1,29-1,31 : protoner i tvillingmethylgrupperne, 1,13 : proton i -CH_7 1,85-2 : 2 protoner i 1-stillingen i cyclopropan, 35 3,9-4 : proton i 0-0¾ -< 5,82-6,01 og fra 6,42 til 6,77: ethyleniske cis-protoner.RMR, ODC1, ppm: 1.29-1.31: protons in the twin methyl groups, 1.13: proton in -CH_7 1.85-2: 2 protons in the 1-position in cyclopropane, 3.9-4: proton in 0-0¾ - <5.82-6.01 and from 6.42 to 6.77: ethylenic cis protons.
UK Ί633Ίΰ Ο 53UK Ί633Ίΰ Ο 53
Præparation 8, (IR« cis«ΔΖ) -2,2 -d imethyl-3 - (3 -oxo -3 -tert« -but oxypropeny 1) --cyelopropancarboxylsyre.Preparation 8 (IR) cis ΔΖ) -2,2-d imethyl-3- (3-oxo-3-tert-but oxypropenyl 1) -cyelopropane carboxylic acid.
Trin A: (lR.cis )-2.2-dimethyl-3-(3-oxo-3-hydroxypropynyl)-5 -oyclopropan-l-carboxylsyre-methylester.Step A: (1R.cis) -2,2-dimethyl-3- (3-oxo-3-hydroxypropynyl) -5-oyclopropane-1-carboxylic acid methyl ester.
I 360 ml tetrahydrofuran indfører man 36,5 g (lR,cis)--2,2-d imethy1-3-(2,2-dibromethenyl)-cyclopropan-l-carboxyl-syremethylester, tilsætter ved -70°C 100 ml 20#'s suspension af butyllithium i cyclohexan, omrører i 10 minutter, lader 10 carbondioxid boble igennem i 30 minutter, lader temperaturen stige til 20°C, hælder reaktionsblandingen i en blanding af vand, is og natriumbiearbonat, ekstraherer med ethylether, vasker med vand, syrner de organiske faser, ekstraherer dem med ether, vasker de forenede organiske faser med vand, ind-15 damper dem til tørhed ved destillation under formindsket tryk, chromatograferer resten på silicagel under eluering med en blanding af cyclohexan og ethylacetat (6:4) tilsat 1# eddikesyre og får 6,8 g (lR,cis)-2,2-dimethyl-3~(3-oxo-3-hy-droxypropynyl)-cyclopropan-l-earboxylsyremethylester.Into 360 ml of tetrahydrofuran 36.5 g (1R, cis) - 2,2-d imethyl-3- (2,2-dibromoethenyl) cyclopropane-1-carboxylic acid methyl ester are added at -70 ° C. 20 # suspension of butyl lithium in cyclohexane, stirring for 10 minutes, bubbling 10 carbon dioxide for 30 minutes, raising the temperature to 20 ° C, pouring the reaction mixture into a mixture of water, ice and sodium bierbonate, extracting with ethyl ether, washing with water, acidifying the organic phases, extracting them with ether, washing the combined organic phases with water, evaporating them to dryness under reduced pressure, chromatographing the residue on silica gel eluting with a mixture of cyclohexane and ethyl acetate (6: 4 ) added 1 # acetic acid and obtained 6.8 g (1R, cis) -2,2-dimethyl-3- (3-oxo-3-hydroxypropynyl) -cyclopropane-1-earboxylic acid methyl ester.
20 Trin B: (IR,cis)-2.2-dimethy 1-3-(3-oxo-3-tert.-butoxypropyn.v 1)--cyclopropan-l-carboxylsyremethylester.Step B: (IR, cis) -2,2-Dimethyl 1-3- (3-oxo-3-tert.-butoxypropynyl) 1-cyclopropane-1-carboxylic acid methyl ester.
I 10 ml ethylacetat indfører man 6,8 g (IR,ois)-2,2--dimethyl-3-(3“Oxo-3-hydroxypropynyl)-cyclopropan-l-carboxyl-sycemethylester, og man tilsætter ved 15°C 13,5 g 0-tert.-butyl-25 -N,JP-diisopropylurinstof, omrører i 2 timer, eliminerer ved filtrering det dannede uopløselige materiale, inddamper filtratet til tørhed, chromatograferer resten på silicagel under eluering med en blanding af cyclohexan og ethylacetat (85ί15) og får 7 g (lR,cis)-2,2-dimethyl-3-(3-oxo-3-tert,-butoxypropy-30 nyl)-cyclopropan-l-carboxylsyremethylester.6.8 g of (IR, ois) -2,2 - dimethyl-3- (3'-Oxo-3-hydroxypropynyl) -cyclopropane-1-carboxylic acid methyl ester are added to 10ml of ethyl acetate and added at 15 ° C. 13.5 g of O-tert.-butyl-25-N, JP-diisopropylurea, stir for 2 hours, eliminate by filtration the insoluble material formed, evaporate the filtrate to dryness, chromatograph the residue on silica gel eluting with a mixture of cyclohexane and ethyl acetate (85ί15) to give 7 g (1R, cis) -2,2-dimethyl-3- (3-oxo-3-tert, -butoxypropynyl) -cyclopropane-1-carboxylic acid methyl ester.
Trin C: (lR.ois.AZ)-2.2-dimethyl-3-(5-oxo-3-tert.-butoxy-l--propenyl)-c.vclopro pan-1-carboxylsy rerne thylester.Step C: (1R.ois.AZ) -2,2-dimethyl-3- (5-oxo-3-tert.-butoxy-1-propenyl) -cyclopropan-1-carboxylic acid ethyl ester.
Man hydrogenerer ved 20°C i nærværelse af 10# palladiumhydroxid på bariumsulfat og 1,4 ml quinolin 7g (lR,cis)-35 -2,2-d imethy1-3-(3-oxo-3-te rt,-butoxypropyny1)-cyclopropan-1- -carboxylsyremethylester i 149 ml ethylacetat. Man filtrerer, vasker filtratet med 1 fl saltsyre og derefter med vand, tør-Hydrogenation at 20 ° C in the presence of 10 # palladium hydroxide on barium sulfate and 1.4 ml of quinoline 7g (1R, cis) -35 -2,2-dimethyl-3- (3-oxo-3-tert-butoxypropynyl) ) -cyclopropane-1-carboxylic acid methyl ester in 149 ml of ethyl acetate. Filtrate, wash the filtrate with 1 µL hydrochloric acid and then with water, dry
DK 163918BDK 163918B
54 rer det og inddamper det til tørhed ved destillation nnder formindsket tryk og får 5,8 g (lR,cis,AZ)-2,2-dimethyl-3--(3-oxo-3-tert, -butoxy-l-propenyl )-cyclopropan-l-carboxyl-syremethylester.54 stirred and evaporated to dryness by distillation under reduced pressure to give 5.8 g (1R, cis, AZ) -2,2-dimethyl-3- (3-oxo-3-tert-butoxy-1- propenyl) -cyclopropane-1-carboxylic acid methyl ester.
5 Trin D: (IR.cis.AZ)-2.2-dimeth.vl-3-(3-oxo-5-tert«-butoxy-1--propenyl )-c.yclopropan-l-carboxylsyre.Step D: (IR.cis.AZ) -2,2-dimethyl-3- (3-oxo-5-tert-butoxy-1-propenyl) -cyclopropane-1-carboxylic acid.
I en blanding af 25 ml methanol og 9,8 ml 1 R vandig natriumhydroxidopløsning indfører man 2,5 g (IR,cis,ΔΖ)-2,2--dimethyl-3-(3-oxo-3-tert.-butoxy-l-propenyl)-cyclopropan-Ι-ΙΟ -carboxylsyremethylester, omrører i 3 timer ved 50°C, afkøler til -75°C, hælder reaktionsblandingen i vand, ekstrahe-rer med ethylether, symer den vandige fase til en pH-værdi på 1 med saltsyre, ekstraherer med ether, inddamper de organiske ekstrakter til tørhed ved destillation under formind-15 sket tryk, chromatograferer resten på silicagel under elue-ring med en blanding af cyclohexan og ethylacetat (7*3) tilsat 1$ eddikesyre og får 1,576 g (lR,cis,AZ)-2,2-dimethyl-3--(3-oxo-3-tert,-butoxypropenyl)-cyclopropan-l-carboxylsyre.To a mixture of 25 ml of methanol and 9.8 ml of 1 R aqueous sodium hydroxide solution is added 2.5 g (IR, cis, ΔΖ) -2,2 - dimethyl-3- (3-oxo-3-tert-butoxy) -l-propenyl) -cyclopropane-Ι-ΙΟ-carboxylic acid methyl ester, stir for 3 hours at 50 ° C, cool to -75 ° C, pour the reaction mixture into water, extract with ethyl ether, simmer the aqueous phase to a pH of 1 with hydrochloric acid, extract with ether, evaporate the organic extracts to dryness by distillation under reduced pressure, chromatograph the residue on silica gel eluting with a mixture of cyclohexane and ethyl acetate (7 * 3) with 1 $ acetic acid and sheep 1.576 g (1R, cis, AZ) -2,2-dimethyl-3- (3-oxo-3-tert-butoxypropenyl) -cyclopropane-1-carboxylic acid.
I.R.spektrum (CHCl,)s 20 Absorption ved 3500 cm , som tilskrives syre-OH (monomer + dimer)I.R. Spectrum (CHCl3) s Absorption at 3500 cm attributed to acid OH (monomer + dimer)
Absorptioner ved 1730 cm"^ og 1695 em“^, som tilskrives syre- og ester-C=0Absorbances at 1730 cm 2 and 1695 cm 2, attributed to acid and ester C = 0
Absorption ved 1628 em""^, som tilskrives konjugeret C=C 25 Absorptioner ved 1390 cm“^ og 1377 cm~^, som tilskrives tvillingmethylgruppemeAbsorption at 1628 cm 2, attributed to conjugated C = C 25 Absorptions at 1390 cm 2 and 1377 cm 2, attributed to the twin methyl groups
Absorption ved 1368 cm"’^', som tilskrives tert.-butyl. Præparation 9.Absorption at 1368 cm 2, attributed to tert-butyl. Preparation 9.
30 (IR. cis «ΔΖ )-2.2-dimethyl-3-(3-isobutyloxy-5-oxo-l-propenyl )--c.vclopropan-l-oarboxylsyre.(IR. Cis-ΔΖ) -2,2-dimethyl-3- (3-isobutyloxy-5-oxo-1-propenyl) -cyclopropane-1-oreboxylic acid.
Trin A: (IR.cis.ΔΖ)-2«2-dimethy1-3-(3-isobutoxy-5-oxo-1-pro-penyl)-cyclopropan-l-carboxylsyre--tept.-buty les ter.Step A: (IR.cis.ΔΖ) -2- [2-dimethyl-3- (3-isobutoxy-5-oxo-1-propenyl) -cyclopropane-1-carboxylic acid tept.-butyl ester.
I 10 ml methylenehlorid og 1 g isobutanol indfører 35 man 4 g (lR,cis,AZ)-2,2-dimethyl-3-(3-hydroxy-3-oxo-l-pro-penyl)-cyclopropan-l-carboxylsyre-tert.-butylester fremstillet efter præparation 4, trin A, og derpå tilsætter man ved 0°C 2,8 g dicyclohexylcarbodiimid og 30 mg dimethylamino- UK Ίϋ^Ιΰ 0 55 pyridin opløst i 10 ml methylenchlorid. Man omrører i 17 timer ved 20°G, eliminerer det uopløselige materiale ved filtrering, inddamper til tørhed véd destillation under formindsket tryk, chromatograferer resten på silicagel under 5 eluering med en blanding af cyclohexan og isopropylether (9:1) og får 2,1 g (lE,cis,AZ)-2,2-dimethyl-3-(3-isobutoxy--3-oxo-l-propenyl)-cyclopropan-l-carboxylsyre-tert.-butyl-ester.Into 10 ml of methylene chloride and 1 g of isobutanol are introduced 4 g of (1R, cis, AZ) -2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid -tert.-butyl ester prepared after Preparation 4, Step A, and then 2.8 g of dicyclohexylcarbodiimide and 30 mg of dimethylamino-UK-pyridine dissolved in 10 ml of methylene chloride are added at 0 ° C. Stir for 17 hours at 20 ° G, eliminate the insoluble material by filtration, evaporate to dryness under reduced pressure, chromatograph the residue on silica gel eluting with a mixture of cyclohexane and isopropyl ether (9: 1) to give 2.1 g (1E, cis, AZ) -2,2-dimethyl-3- (3-isobutoxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid tert-butyl ester.
Trin B: (IB. cl s«ΔΖ) -2.2 -d ime thyl-3 - (3 -is obut oxy-3 -oxo-l-pro-10 pen.yl )-cyolopropan-l-carboxylsyre.Step B: (IB. Cl s sΔΖ) -2,2-dimethyl-3- (3-isobutoxy-3-oxo-1-propenyl) -cyolopropane-1-carboxylic acid.
I 20 ml toluen indfører man 2,1 g (lB,cis,AZ)-2,2--dimethyl-3-(3-isobutoxy-3-oxo-l-propenyl)-cyclopropan-l--carboxylsyre-tert.-butylester og 0,1 g p-toluensulfonsyre, og man opvarmer til tilbagesvaling og opretholder denne i 15 20 minutter, inddamper til tørhed ved destillation under formindsket tryk, chromatograferer på silicagel under eluering med en blanding af hexan og ethylacetat (7:3) tilsat 1# eddikesyre og får 1,53 g (lE,cis,AZ)-2,2-dimethyl-3-(3-butoxy--3-oxo-l-propenyl)-eyclopropan-l-carboxylsyre.2.1 g of (1B, cis, AZ) -2,2-dimethyl-3- (3-isobutoxy-3-oxo-1-propenyl) -cyclopropane-1-carboxylic acid tert are introduced into 20 ml of toluene. -butyl ester and 0.1 g of p-toluenesulfonic acid, heated to reflux and maintained for 15 minutes, evaporated to dryness under reduced pressure, chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (7: 3) added 1 # acetic acid and obtained 1.53 g (1E, cis, AZ) -2,2-dimethyl-3- (3-butoxy-3-oxo-1-propenyl) -eyclopropane-1-carboxylic acid.
20 I. B.spektrum (chloroform):B. spectrum (chloroform):
Absorption ved 3300 cm”'*', som tilskrives syre-0H Absorption ved 1730 cm*"1, 1706 cm"*1 og 1694 cm*"1, som tilskrives syre-C=0 og konjugeret ester Absorption ved 1630 cm**1, som tilskrives C=C (ΔΖ) 25 Absorption ved 1390 cm”1 og 1380 cm”1, som tilskrives tvilling- methylgrupperoe.Absorption at 3300 cm ”', attributed to acid-0H Absorption at 1730 cm *", 1, 1706 cm "*, 1 and 1694 cm *" 1, attributed to acid C = 0, and conjugated ester Absorption at 1630 cm cm ** 1, which is attributed to C = C (ΔΖ) 25 Absorption at 1390 cm ”1 and 1380 cm” 1, which is attributed to twin methyl groups.
Præparation 10, (IB. cis. ΔΖ) -2.2 -d ime thyl-3 - (3 -n-butoxy-3 -oxo -1-propenyl) -30 -cyclopropancarboxylsyre.Preparation 10, (IB. Cis. ΔΖ) -2,2-dimethyl-3- (3-n-butoxy-3-oxo-1-propenyl) -30-cyclopropane carboxylic acid.
Trin A: (IB«cis )-2.2-dimethyl-3-(3-n-butoxy-3-oxo-l-propynyl)--cyclopropancarboxylsyre-tert. -but.vles ter.Step A: (1B) cis -2,2-Dimethyl-3- (3-n-butoxy-3-oxo-1-propynyl) -cyclopropane carboxylic acid tert. -but.vles ter.
Man blander 4 g (1E,cis)-2,2-dimethyl-3-(3-hydroxy--3-oxo-l-propynyl)-cyclopropancarboxylsyre-tert.-butylester, 35 40 ml methylenchlorid og 6 mg 4-diethylaminopyridin, og der på tilsætter man 3,4 g dicyclohexylearbodiimid. Efter 30 minutters omrøring under indifferent atmosfære tilsætter man4 g of (1E, cis) -2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propynyl) -cyclopropane carboxylic acid tert-butyl ester, 40 ml of methylene chloride and 6 mg of 4-diethylaminopyridine are mixed. and 3.4 g of dicyclohexyl arbodiimide are added. After stirring for 30 minutes under inert atmosphere, add
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56 i løbet af 5 minutter 4 ml af en blanding af n-butanol og methylenehlorid (1:1) og fortsætter omrøringen i 3 timer ved stuetemperatur. Man frafiltrerer det dannede dieyclohexyl-urinstof, inddamper filtratet til tørhed under formindsket 5 tryk og chromatograferer resten på silicagel under eluering med en blanding af cyclohexan og ethylacetat (9*1)· Der fås 4,7 g af den forventede forbindelse.56 over 5 minutes 4 ml of a mixture of n-butanol and methylene chloride (1: 1) and continue stirring for 3 hours at room temperature. The resulting dieyclohexyl urea is filtered off, the filtrate is evaporated to dryness under reduced pressure and the residue is chromatographed on silica gel eluting with a mixture of cyclohexane and ethyl acetate (9 * 1). 4.7 g of the expected compound are obtained.
Trin B: (IR. cis. ΔΖ )-2.2-dimethyl-3-(3-n-butoxy-5-oxo-l-pro-penyl)-oyclopropancarboxylsyre-tert.-butyleBter.Step B: (IR. Cis. ΔΖ) -2,2-Dimethyl-3- (3-n-butoxy-5-oxo-1-propenyl) oyclopropane carboxylic acid tert-butyl Butter.
10 Man omrører under hydrogenatmosfære i 15 minutter 800 mg palladiumhydroxid på bariumsulfat i 20 ml ethylacetat og tilsætter derpå 4,7 g af den ovenfor fremstillede forbindelse i 50 ml ethylacetat og 0,8 ml quinolin og lader henstå under hydrogenatmosfære i 30 minutter. Man filtrerer, 15 vasker filtratet med 1 Bf saltsyre og derefter med vand, tørrer, inddamper til tørhed under formindsket tryk og chromato-graferer resten på silicagel under eluering med en blanding af cyclohexan og ethylacetat (95*5). Der fås 3,4 g af den forventede forbindelse.Hydrogen atmosphere is stirred for 15 minutes under 800 mg of palladium hydroxide on barium sulfate in 20 ml of ethyl acetate and then 4.7 g of the above compound is added in 50 ml of ethyl acetate and 0.8 ml of quinoline and left under hydrogen atmosphere for 30 minutes. The filtrate is washed, washed with 1 Bf hydrochloric acid and then with water, dried, evaporated to dryness under reduced pressure and chromatographed on silica gel eluting with a mixture of cyclohexane and ethyl acetate (95 * 5). 3.4 g of the expected compound are obtained.
20 Trin C: (IR,cis.ΔΖ)-2.2-dimethyl-3-(3-n-butoxy-3-oxo-l-prope- n.vl )-c.vclopropancarboxylsyre.Step C: (IR, cis.ΔΖ) -2,2-dimethyl-3- (3-n-butoxy-3-oxo-1-propene-nyl) -cyclopropane carboxylic acid.
Man omrører 3,3 g af den ovenfor fremstillede forbindelse med 350 mg p-toluensulfonsyre i 40 ml toluen. Man opvarmer til tilbagesvaling indtil ophør af gasudviklingen af iso-25 butylen, hvilket varer ea. 40 minutter. Man inddamper til tørhed under formindsket tryk, ehromatograferer resten på silicagel under eluering med en blanding af cyclohexan, ethylacetat og eddikesyre (75*25*1) og får 2 g af den forventede forbindelse.3.3 g of the above-prepared compound are stirred with 350 mg of p-toluenesulfonic acid in 40 ml of toluene. It is heated to reflux until the gas evolution of iso-butylene is stopped, which lasts for example. 40 minutes. Evaporate to dryness under reduced pressure, ehromatograph the residue on silica gel eluting with a mixture of cyclohexane, ethyl acetate and acetic acid (75 * 25 * 1) to obtain 2 g of the expected compound.
30 N.M.R., CPC15, ppm: 1,26 og 1,3 : protoner i methylgrupperne i 2-stillingen i cyclopropan 1,85-1,99 * proton i 1-stillingen i cyclopropan 3,13 til 3,47 : proton i 3-stillingen i cyclopropan 35 6,4-6,57 og 6,59-6,75 * proton i 1-stillingen i allylkæden 5,8-5,99 * proton i 2-stillingen i allylkædenNMR, CPC15, ppm: 1.26 and 1.3: protons in the methyl groups at the 2-position in cyclopropane 1.85-1.99 * proton at the 1-position in cyclopropane 3.13 to 3.47: proton in 3 position in cyclopropane 35 6.4-6.57 and 6.59-6.75 * proton at the 1-position in the allyl chain 5.8-5.99 * proton at the 2-position in the allyl chain
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Præparation 11.Preparation 11.
(lR.cis.AZ)-2,2-dimethyl-3-(3-cyclopento:xy-5-oxo-l-propenyl)--cvclopropan-l-oarboxylsyre.(LR.cis.AZ) -2,2-dimethyl-3- (3-cyclopento: xy-5-oxo-l-propenyl) - cvclopropan-l-oarboxylsyre.
Trin A: (IR. ois«ΔΖ)-2.2-dimethyl-3-(3-cyclopentoxy-3-oxo-l-5 -propenyl)-cyclopropan-l-carboxylsyre-tert.-butyl- ester.Step A: (IR) [α] -2 -2,2-Dimethyl-3- (3-cyclopentoxy-3-oxo-1-5-propenyl) -cyclopropane-1-carboxylic acid tert-butyl ester.
I 15 ml methylenchlorid indfører man 4 g (lR,cis,AZ)--2,2-d ime thyl-3-(3-hydroxy-3-oxo-l-propenyl)-eyclopropan-1--carboxylsyre-tert.-butylester og 1,43 g cyclopentanol, og 10 man tilsætter ved 0°C 3,43 g cyclohexylcarbodiimid og 40 mg dimethylaminopyridin opløst i 10 ml methylenchlorid, omrører suspensionen ved 20°C i 17 timer, eliminerer det uopløselige materiale ved filtrering, inddamper filtratet til tørhed ved destillation under formindsket tryk, chromatograferer resten 15 på silicagel under eluering med en blanding af cyclohexan og isopropylether (0:1) og får 1,38 g (IR,cis,ΔΖ)-2,2-dimethyl--3-(3-cyclopentoxy-3-oxo-l-propenyl )-eyclopropan-l-carboxyl-syre-tert.-butylester med smp. 57°C.Into 15 ml of methylene chloride are introduced 4 g (1R, cis, AZ) - 2,2-dimethyl-3- (3-hydroxy-3-oxo-1-propenyl) -eyclopropane-1-carboxylic acid tert. -butyl ester and 1.43 g of cyclopentanol, and 10 ml of 3.43 g of cyclohexylcarbodiimide and 40 mg of dimethylaminopyridine dissolved in 10 ml of methylene chloride are added, stirring the suspension at 20 ° C for 17 hours, eliminating the insoluble material by filtration, evaporating the filtrate to dryness under reduced pressure, chromatograph the residue 15 on silica gel eluting with a mixture of cyclohexane and isopropyl ether (0: 1) to give 1.38 g (IR, cis, ΔΖ) -2,2-dimethyl-3 - (3-cyclopentoxy-3-oxo-1-propenyl) -eyclopropane-1-carboxylic acid tert-butyl ester, m.p. 57 ° C.
Trin B: (IR. ois. ΔΖ) -2.2-dimeth.vl-3-(3-cyclopentoxy-3-oxo-l-20 -propenyl)-cyclopropan-l-carboxylsyre.Step B: (IR. Ois. ΔΖ) -2,2-dimethyl-3- (3-cyclopentoxy-3-oxo-1-20-propenyl) -cyclopropane-1-carboxylic acid.
I 25 ml toluen indfører man 2,54 g (IR,cis,ΔΖ)-2,2--d ime thyl-3-(3-cyclopentoxy-3-oxo-l-propenyl)-eyclopropan--1-carboxylsyre-tert,-butylester og 0,1 g p-toluensulfonsyre, og man opvarmer til tilbagesvaling og opretholder tilbagesva-25 lingen i 20 minutter, inddamper til tørhed ved destillation under formindsket tryk, chromatograferer resten på silicagel under eluering med en blanding af hexan og ethylacetat (7:3) tilsat 1# eddikesyre og får 1,82 g (IR,cis,ΔΖ)-2,2-dimethyl--3-(3-cyclopentoxy-3-oxo-l-propenyl)-cyclopropan-l-carboxyl-30 syre.2.54 g (IR, cis, ΔΖ) -2,2-dimethyl-3- (3-cyclopentoxy-3-oxo-1-propenyl) -eyclopropane-1-carboxylic acid are added in 25 ml of toluene. tert, -butyl ester and 0.1 g of p-toluenesulfonic acid, heating to reflux and maintaining the reflux for 20 minutes, evaporating to dryness under reduced pressure, chromatographing the residue on silica gel eluting with a mixture of hexane and ethyl acetate. (7: 3) added 1 # acetic acid to give 1.82 g (IR, cis, ΔΖ) -2,2-dimethyl-3- (3-cyclopentoxy-3-oxo-1-propenyl) -cyclopropane-1- carboxylic acid.
I.R.spektrum (chloroform):I.R. spectrum (chloroform):
Absorption ved 3510 cm-1, som tilskriver syre-OH Absorptioner ved 1735 cm"1 og 1702 cm"1, som tilskrives syre-C:=0 og konjugeret esterAbsorption at 3510 cm -1 attributed to acid OH Absorbances at 1735 cm -1 and 1702 cm 1 attributed to acid C: = 0 and conjugated ester
35 Absorption ved 1632 cm"1, som tilskrives konjugeret Cf=CAbsorption at 1632 cm -1, attributed to conjugated Cf = C
-1-1
Absorption ved 1380 cm , som tilskrives tvillingmethylgrup- pemeAbsorption at 1380 cm, which is attributed to the twin methyl groups
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Præparation 12.Preparation 12.
(IR« trans«ΔΖ) -2,2 -d jme thy1-3 -(3-( 1-methyle thoxy) -3 -oxo-1--propenyl)-oyclopropancarboxylsyre.(IR «trans «ΔΖ) -2,2-dimethyl-3- (3- (1-methylthoxy) -3-oxo-1-propenyl) -ocyclopropane carboxylic acid.
Trin A: (IR. trans)-2.2-dimethy 1-5-(5-h.vdroxy-3-oxo-l-propy-5 nyl)-oyolopropancarboxylsyre-tert.-butylester.Step A: (IR. Trans) -2,2-Dimethyl 1-5- (5-hydroxy-3-oxo-1-propynyl) -oyolopropane carboxylic acid tert-butyl ester.
Man arbejder som i trin A i præparation 2 ud fra 40 g (lE,trans)-2,2-dimethyl-3-(2,2-dibromvinyl)-cyclopropan-carboxylsyre-tert.-butylester. Efter ehrornatografi på sili-eagel af råproduktet under eluering med cyclohexan, ethyl-10 acetat og eddikesyre (6:4:0,2) får man 19,2 g af den forventede forbindelse.As in Step A of Preparation 2, 40 g of (1E, trans) -2,2-dimethyl-3- (2,2-dibromovinyl) -cyclopropane-carboxylic acid tert-butyl ester is used. After ehrornatography on silica gel of the crude product eluting with cyclohexane, ethyl acetate and acetic acid (6: 4: 0.2), 19.2 g of the expected compound are obtained.
Trin B: (lR.t rans) -2.2 -d ime tb y 1-3 - (3 -(1-me thy le thoxy) -3 -oxo --1-propynyl)-oyclopropancarboxylsyre-tert.-butylester. Man blander 3,6 g af den i forrige ttin fremstillede 15 forbindelse med 20 ml ethylacetat, tilsætter 3 g 0-isopropyl--diis opr opy lie ourins tof og omrører i 16 timer under tilbagesvaling. Efter afkøling til stuetemperatur filtrerer man og inddamper filtratet til tørhed under formindsket tryk og får 2,7 g af den forventede forbindelse.Step B: (1R.t.R.) -2,2-D ime tb y 1-3 - (3- (1-methylthoxy) -3-oxo-1-propynyl) oyclopropane carboxylic acid tert-butyl ester. 3.6 g of the compound obtained in the previous ttin are mixed with 20 ml of ethyl acetate, 3 g of 0-isopropyl diisopropylamine is added and the mixture is stirred at reflux for 16 hours. After cooling to room temperature, the filtrate is dried and evaporated to dryness under reduced pressure to give 2.7 g of the expected compound.
20 Trin C: (lR.trans.AZ)-2.2-dimethyl-3-(3-(l-methylethoxy)--5-oxo-l-propenyl)-oyolopropancarboxylsyre-tert.--butvlester.Step C: (1R.trans.AZ) -2,2-dimethyl-3- (3- (1-methylethoxy) -5-oxo-1-propenyl) -oyolopropane carboxylic acid tert.-butyl ester.
Man hydrogenerer 2,7 g af den i forrige trin fremstillede forbindelse i 50 ml ethylacetat i nærværelse af 0,55 g 25 palladiumhydroxid (10$) på bariumsulfat og 0,55 ml quinolin. Man filtrerer, vasker filtratet med 1 li saltsyre og derefter med vand indtil neutralitet, tørrer og inddamper til tørhed under formindsket tryk. Per fås 2,18 g af den forventede forbindelse.2.7 g of the compound prepared in the previous step is hydrogenated in 50 ml of ethyl acetate in the presence of 0.55 g of palladium hydroxide ($ 10) on barium sulfate and 0.55 ml of quinoline. The filtrate is washed, the filtrate is washed with 1 liter of hydrochloric acid and then with water until neutrality, dried and evaporated to dryness under reduced pressure. 2.18 g of the expected compound are obtained per.
30 Trin P: (IR.trans.AZ)-2.2-dimeth.v1-3-(3-(1-methylethoxy)--3-oxo-l-propenyl )-c.yclopropancarboxylsyre.Step P: (IR.trans.AZ) -2,2-dimethyl-3- (3- (1-methylethoxy) -3-oxo-1-propenyl) -cyclopropane carboxylic acid.
Man tilbagesvaler 2,18 g af det i forrige trin fremstillede stof med 20 ml toluen og 0,2 g p-toluensulfonsyre. Efter afkøling til stuetemperatur vasker man den organiske 35 fase, tørrer den og inddamper den til tørhed under formindsket tryk. Per fås 1,6 g af den forventede forbindelse.2.18 g of the substance prepared in the previous step is refluxed with 20 ml of toluene and 0.2 g of p-toluenesulfonic acid. After cooling to room temperature, the organic phase is washed, dried and evaporated to dryness under reduced pressure. 1.6 g of the expected compound are obtained.
5959
LIIS. 1009 IO DLiis. 1009 IO D
Præparation 13« 3-phenoxy-g-hydroxybenzenethanthioamid« I en opløsning af 200 g a-cyan-3-phenoxybenzyl-alkohol i 200 ml toluen og 4,5 ml triethylamin lader man 5 boble bydrogensulfid i 22 timer, hvorpå man hælder reaktion s bland ingen i en vandig 1 N saltsyre, fraskiller den organiske fase ved dekantering, vasker den med vand, tørrer den, inddamper den til tørhed ved destillation under formindsket tryk, chromatograferer resten på silicagel under elue-10 ring med en blanding af benzen og ethylacetat (8:2), krystalliserer af isopropylether og får 18,5 g 3-phenoxy-oc-hydroxy-benzenethanthioamid med smp. 70°C, I.R.spektrum (chloroform):Preparation 13 «3-Phenoxy-g-hydroxybenzenethethioamide« In a solution of 200 g of α-cyan-3-phenoxybenzyl alcohol in 200 ml of toluene and 4.5 ml of triethylamine, 5 bubbles of city-drug sulphide are allowed to react for 22 hours. do not mix in an aqueous 1N hydrochloric acid, separate the organic phase by decantation, wash it with water, dry it, evaporate it to dryness under reduced pressure, chromatograph the residue on silica gel eluting with a mixture of benzene and ethyl acetate (8: 2), crystallizes from isopropyl ether to give 18.5 g of 3-phenoxy-oc-hydroxy-benzenethethioamide, m.p. 70 ° C, I.R. Spectrum (chloroform):
Absorption ved 3600 cm”1, som tilskrives frit og associeretAbsorption at 3600 cm ”1, which is freely attributed and associated
15 OHOH
Absorptioner ved 3478 og 3360 cm”1, som tilskrives -JTH9 —iAbsorbances at 3478 and 3360 cm ”1, attributed to -JTH9 -i
Absorptioner ved 1670, 1578 og 1477 cm , som tilskrives de aromatiske ringe og -CS-NHg spektrum (deuterochloroform): 20 toppe ved 3,97-4,03 ppm, som tilskrives hydrogenet i hydroxyl toppe ved 5,18-5,25 ppm, som tilskrives det hydrogen, som bæres ved carbonatomet i α-stilling til -CS- toppe fra 6,92 til 7,58 ppm, som tilskrives hydrogenat orneme 25 i de aromatiske ringe top ved 7,5 ppm, som tilskrives hydrogenat orne me i-STHgAbsorbances at 1670, 1578 and 1477 cm attributed to the aromatic rings and -CS-NHg spectrum (deuterochloroform): 20 peaks at 3.97-4.03 ppm attributed to the hydrogen in hydroxyl peaks at 5.18-5.25 ppm attributed to the hydrogen carried at the carbon atom in the α position to -CS- peaks from 6.92 to 7.58 ppm attributed to hydrogenate carvings 25 in the aromatic rings at 7.5 ppm attributed to hydrogenated carbons me i-STHg
Præparation 14« (2-phenoxy-4-thiadiazolyl)-methanol.Preparation 14 '(2-phenoxy-4-thiadiazolyl) -methanol.
30 Trin A: 2-phenoxythiazol-4-carboxylsyreethylester«Step A: 2-Phenoxythiazole-4-carboxylic acid ethyl ester
Man blander 2 g 2-chlorthiazol-4-carboxylsyreethyl-ester, 50 ml dimethylformamid, 2,5 ml hexamethylphosphortri-amid og 1,5 g natriumiodid, opvarmer reaktionsblandingen til 100°C, ^holder den 1 time på denne temperatur, afkøler til 35 20°G, indfører portionsvis 1,32 g kaliumphenat, opvarmer re aktionsblandingen til ti lb age svaling i 1 time 30 minujtter, tilsætter 0,66 g kaliumphenat, opretnolder tilbagesvalingen i 1 ti-2 g of 2-chlorothiazole-4-carboxylic acid ethyl ester, 50 ml of dimethylformamide, 2.5 ml of hexamethylphosphoric triamide and 1.5 g of sodium iodide are heated, the reaction mixture is heated to 100 ° C, kept at this temperature for 1 hour, cooled to 35 20 ° G, introduces portionwise 1.32 g of potassium phenate, heats the reaction mixture to ten lb. of cooling for 1 hour 30 minutes, adds 0.66 g of potassium phenate, maintains the reflux for 1 hour.
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60 me 30 minutter, afkøler, tilsætter vand og ethylacetat, eks-traherer med ethylacetat, vasker de organiske faser med vand og inddamper dem til tørhed, chromat ograf erer resten på si-lieagel under eluering med en blanding af hexan, isopropyl-5 ether og triethylamin (7:3:1) og får 1,08 g 2-phenoxythia-zol-4-carboxylsyreethylester med smp. 67°C.60 ml for 30 minutes, cool, add water and ethyl acetate, extract with ethyl acetate, wash the organic phases with water and evaporate to dryness, chromatograph and evaporate the residue on silica gel eluting with a mixture of hexane, isopropyl ether and triethylamine (7: 3: 1) to give 1.08 g of 2-phenoxythiazole-4-carboxylic acid ethyl ester, m.p. 67 ° C.
Trin B: (2-phenox-V-4-thiazolyl)-methanol.Step B: (2-Phenox-V-4-thiazolyl) -methanol.
I en opløsning af 12 g 2-phenoxythiazol-4-carboxyl-syreethylester i 60 ml toluen indfører man langsomt ved -10°C 10 54 ml toluenopløsning af diethylnatriumaluminiumhydrid med en koncentration på 2 mol pr. liter, omrører i 1 time ved -5°C, indfører ved -20°C 80 ml 2 I saltsyre og derefter vand, eliminerer det dannede uopløselige materiale ved filtrering, dekanterer filtratet, vasker den organiske opløsning med vand, 15 med 2 IT natriumhydroxid opløsning og derefter atter med vand, inddamper til tørhed, cfaromatograferer resten på silicagel under eluering med en blanding af methylehchlorid og ethylacetat (8:2) og får 8,15 g (2-phenoxy-4-thiazolyl)-methanol.To a solution of 12 g of 2-phenoxythiazole-4-carboxylic acid ethyl ester in 60 ml of toluene is slowly introduced at -10 ° C 54 ml of toluene solution of diethyl sodium aluminum hydride at a concentration of 2 moles per ml. liter, stirring for 1 hour at -5 ° C, introducing at -20 ° C 80 ml of 2 L hydrochloric acid and then water, eliminating the insoluble material formed by filtration, decanting the filtrate, washing the organic solution with water, 15 with 2 IT sodium hydroxide solution and then again with water, evaporating to dryness, chromatographing the residue on silica gel eluting with a mixture of methylene chloride and ethyl acetate (8: 2) to give 8.15 g (2-phenoxy-4-thiazolyl) -methanol.
I.R. spektrum (chloroform): 20 Absorption ved 3590 cm”1, som tilskrives hydroxylI.R. spectrum (chloroform): Absorption at 3590 cm -1, attributed to hydroxyl
Absorptioner ved 1551, 1530, 1503 og I486 cm”1, som tilskrives den aromatiske ring og thiazol Absorption ved 690 cm”1, som tilskrives phenyl (deformation).Absorbances at 1551, 1530, 1503 and I486 cm "1, attributed to the aromatic ring and thiazole Absorption at 690 cm" 1, attributed to phenyl (deformation).
25 H.M.R.spektrum (deuterochloroform): top ved 4,5 ppm, som tilskrives hydrogenatorneme i GHg-O top ved 3*5 ppm, som tilskrives hydrogenet i -OH top ved 6,66 ppm, som tilskrives det thiazoliske hydrogen toppe fra 7,10 til 7,50 ppm, som tilskrives hydrogenatomeme 30 i den aromatiske ringHMR spectrum (deuterochloroform): peak at 4.5 ppm, which is attributed to the hydrogenators in GHg-O peak at 3 * 5 ppm, which is attributed to the hydrogen in -OH peak at 6.66 ppm, which is attributed to the thiazolic hydrogen peaks from 7, 10 to 7.50 ppm, which is attributed to the hydrogen atoms 30 in the aromatic ring
Præparation 15.Preparation 15.
(BS)-tt-cyan-(2-phenoxy-4-thiazolvl)-methanol.(BS) -tt-cyano- (2-phenoxy-4-thiazolyl) methanol.
Trin A: (2-phenoxy-4-thiazolvl)-methanal.Step A: (2-Phenoxy-4-thiazolyl) -methanal.
35 I en opløsning af 4,6 g (2-phenoxy-4-thiazolyl)-me thanol indfører man 19,1 g mangandioxid, omrører i 17 timer ved 40°0 og derefter i 3 timer ved 60°C, eliminerer den uop- 61In a solution of 4.6 g of (2-phenoxy-4-thiazolyl) methanol, 19.1 g of manganese dioxide is introduced, stirred for 17 hours at 40 ° C and then for 3 hours at 60 ° C, eliminating the - 61
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løselige rest ved filtrering, inddamper til tørhed under formindsket tryk, chromatograferer resten på silicagel under eluering med en blanding af methylenchlorid og ethylacetat (8:2) og får 2,6 g (2-phenoxy-4-thiazolyl)-methanal med smp.soluble residue by filtration, evaporating to dryness under reduced pressure, chromatographing the residue on silica gel eluting with a mixture of methylene chloride and ethyl acetate (8: 2) to give 2.6 g (2-phenoxy-4-thiazolyl) -methanal, m.p.
5 63°C.63 ° C.
Trin B: (RS )-q-cyan-(2-phenoxy-4-thiazolyl)-methanol.Step B: (RS) -q-Cyan- (2-phenoxy-4-thiazolyl) -methanol.
I en opløsning af 0,85 g natriumcyanid i 5 ml vand indfører man ved 10°C 2,4 g (2-phenoxy-4-thiazolyl)-methanal opløst i 10 ml ether, omrører i 10 minutter, indfører dråbe-10 vis ved 0°C en blanding af 2 ml koncentreret vandig svovlsyreopløsning og 3 ml vand, omrører i 2 timer ved 0°C, fraskiller den organiske fase ved dekantering, vasker med vand, tørrer, inddamper til tørhed under formindsket tryk, sætter isopro-pylether til resten, frasuger udfældningen, tørrer den og får 15 2,28 g (RS)-q-cyan-(2-phenoxy-4-thiazolyl)-methanol.In a solution of 0.85 g of sodium cyanide in 5 ml of water, 2.4 g of (2-phenoxy-4-thiazolyl) -methanal dissolved in 10 ml of ether is added at 10 ° C, stirred for 10 minutes, introduced dropwise. at 0 ° C a mixture of 2 ml of concentrated aqueous sulfuric acid solution and 3 ml of water, stirring for 2 hours at 0 ° C, separating the organic phase by decantation, washing with water, drying, evaporating to dryness under reduced pressure, adding isopropyl ether to the residue, sucks the precipitate, dries it and gives 2.28 g (RS) -q-cyano- (2-phenoxy-4-thiazolyl) -methanol.
I, R.spektrum (chloroform):I, R. spectrum (chloroform):
Absorption ved 3580 cm”1, som tilskrives hydroxylgruppen Absorption ved 3550 cm”1, som tilskrives den associerede hy- d roxylgruppe 20 Absorption ved 1590, 1504 og 1487 em”1, som tilskrives den aromatiske ring og thiazol.Absorption at 3580 cm "1, which is attributed to the hydroxyl group Absorption at 3550 cm" 1, which is attributed to the associated hydroxyl group 20 Absorption at 1590, 1504 and 1487 cm "1, which is attributed to the aromatic ring and thiazole.
li.M.R.spektrum (deuterochloroform): top ved 4,08 ppm, som tilskrives hydrogenet i -OHli.M.R. Spectrum (deuterochloroform): peak at 4.08 ppm attributed to the hydrogen in -OH
top ved 5,41 ppm, som tilskrives hydrogenet i 0Ξ-0Η 25 top ved 7,33 ppm, som tilskrives hydrogenatomeme i phenyl top ved 7,0 ppm, som tilskrives det thiazoliske hydrogen.peak at 5.41 ppm, which is attributed to the hydrogen in 0Ξ-0Η 25 peak at 7.33 ppm, which is attributed to the hydrogen atoms in phenyl peak at 7.0 ppm, which is attributed to the thiazolic hydrogen.
Præparation 16.Preparation 16.
3-Phenoxy-4-fluor-g-methylbenz.vlalkohol.3-phenoxy-4-fluoro-g-methylbenz.vlalkohol.
30 Ved 20°C sætter man 15,8 ml af en 2,6 M opløsning af methylmagnesiumiodid i ether til en blanding indeholdende 8 g 3-(4-fluorphenoxy)-benzaldehyd i 50 ml ethylether. Man lader henstå 1 time ved stuetemperatur, hælder blandingen i en vandig ammoniumchloridopløsning, dekanterer, ekstraherer med 35 ether og får den forventede forbindelse, som man krystalliserer af isopropylether. Smp. 64°C.At 20 ° C, 15.8 ml of a 2.6 M solution of methyl magnesium iodide in ether are added to a mixture containing 8 g of 3- (4-fluorophenoxy) benzaldehyde in 50 ml of ethyl ether. Allow to stand for 1 hour at room temperature, pour the mixture into an aqueous ammonium chloride solution, decant, extract with 35 ether and obtain the expected compound crystallized from isopropyl ether. Mp. 64 ° C.
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Eksempler på præparater«Examples of preparations «
Eksempel A: Fremstilling af et opløseligt koncentrat.Example A: Preparation of a soluble concentrate.
Man fremstiller en homogen blanding af:A homogeneous mixture of:
Forbindelsen ifølge eksempel 1 0,25 g 5 piperonylbutoxid 1 gThe compound of Example 1 is 0.25 g of piperonyl butoxide 1 g
Tween 80 0,25 gTween 80 0.25 g
Topanol A 0,1 gTopanol A 0.1 g
Vand 98,4 g 10 Eksempel B: Fremstilling af et emulgerbart koncentrat.Water 98.4 g Example B: Preparation of an emulsifiable concentrate.
Man blander grundigt:You mix thoroughly:
Forbindelsen ifølge eksempel 1 0,015 g pipe ronylbut oxid 0,5 gThe compound of Example 1 is 0.015 g of pipe ronyl but oxide 0.5 g
Topanol A 0,1 g 15 rylen 95,885 gTopanol A 0.1 g rylene 95.885 g
Tween 80 3,5 gTween 80 3.5 g
Eksempel C: Fremstilling af et emulgerbart koncentrat:Example C: Preparation of an emulsifiable concentrate:
Man foretager en homogen blanding af:A homogeneous mixture of:
Forbindelsen ifølge eksempel 1 1,5 g 20 Tween 80 20 gThe compound of Example 1 1.5 g 20 Tween 80 20 g
Topanol A 0,1 g xylen 78,4 gTopanol A 0.1 g xylene 78.4 g
Eksempel 3): Fremstilling af et røgpræparat.Example 3): Preparation of a smoke preparation.
Man blander homogent: 25 Forbindelsen ifølge eksempel 1 0,25 g tabupræparat (pyrethrumkvas) 25 g cederbladpulver 40 g fyrresavsmuld 33,75 g brillantgrønt 0,5 g 30 p-nitrophenol 0,5 g 35 63Homogeneously mixed: 25 The compound of Example 1 0.25 g taboo (pyrethrum quas) 25 g cedar leaf powder 40 g pine sawdust 33.75 g brilliant green 0.5 g 30 p-nitrophenol 0.5 g 35 63
UN 1009 ΙΟ DUN 1009 ΙΟ D
Undersøgelse af aktiviteten af forbindelser ifølge opfindelsen på parasitter.Investigation of the activity of compounds of the invention on parasites.
Eksempel I. Undersøgelse af den letale virkning af forbindelserne ifølge eksempel 1-8 på stueflue« 5 ‘ Porsøgsinsekterne er hun s tue fluer af en pyrethrenoid- følsom stamme, som er opdrættet ved 22-23°C og 60-65# relativ luftfugtighed og er 4-5 dage gamle. Man arbejder ved topisk applikation af 1 μΐ acetoneopløsning på insekternes dorsale thorax ved hjælp af Arnold's mikromanipulator. Man benytter 10 50 individer for hver dosis af den undersøgte forbindelse.Example I. Examination of the lethal effect of the compounds of Examples 1-8 on housefly 5 The test insects are female flies of a pyrethrenoid sensitive strain reared at 22-23 ° C and 60-65% relative humidity and is 4-5 days old. Topical application of 1 μΐ acetone solution to the insect's dorsal thorax is performed using Arnold's micromanipulator. 10 50 individuals are used for each dose of the compound studied.
Man foretager kontrol for dødeligheden 24 timer efter behandlingen.Mortality is checked 24 hours after treatment.
Man konstaterer, at forbindelserne ved den benyttede prøve har en god letal/tirkning.It is found that the compounds in the sample used have a good lethal / twitching.
15 Eksempel II. Undersøgelse af den letale aktivitet af forbindelserne ifølge eksempel 1-8 på larver af Spodop-tera littoralis.Example II. Examination of the lethal activity of the compounds of Examples 1-8 on larvae of Spodoptera littoralis.
Porsøgene udføres ved topisk applikation af en acetoneopløsning ved hjælp af Arnold's mikromanipulator på larver-20 nes dorsale thorax. Man benytter 15 larver for hver dosis af den undersøgte forbindelse. De benyttede larver er larver i fjerde larvestadium, dvs. ca. 10 dage gamle, når de opdrættes ved 24°C og 65# luftfugtighed. Efter behandlingen anbringes individerne på et kunstigt næringsmilieu (Poitout's milieu).The assays are performed by topically applying an acetone solution using Arnold's micromanipulator on the dorsal thorax of the larvae. 15 larvae are used for each dose of the compound studied. The larvae used are larvae in the fourth larval stage, ie. ca. 10 days old when raised at 24 ° C and 65 # humidity. After treatment, the individuals are placed in an artificial nutritional environment (Poitout's environment).
25 Man foretager kontrol af dødeligheden 48 timer efter behandlingen.25 Mortality is checked 48 hours after treatment.
Man konstaterer, at forbindelserne ved den benyttede prøve har en god letal virkning.It is found that the compounds of the sample used have a good lethal effect.
Eksempel III. Undersøgelse af aktiviteten af forbindelserne 30 ifølge eksempel 1-8 på larver af Epilachna varivestris.Example III. Investigation of the activity of compounds 30 of Examples 1-8 on larvae of Epilachna varivestris.
Porsøgene udføres ved topisk applikation på samme måde som ved fluerne og larverne af Spodoptera. Man benytter larver i det næstsidste larvestadium, og efter behandlingen er-35 næres larverne på bønneplanter. Man foretager kontrol af dødeligheden 72 timer efter behandlingen.The tests are performed by topical application in the same way as the flies and larvae of Spodoptera. Larvae are used in the penultimate larval stage and after treatment, the larvae are nourished on bean plants. Mortality is checked 72 hours after treatment.
Man konstaterer at forbindelserne ved den benyttede prøve har en god letal virkning.It is found that the compounds in the sample used have a good lethal effect.
DK 163918BDK 163918B
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Eksempel IV, Undersøgelse af chokvirkningen på stueflue«Example IV, Investigation of the shock effect on housefly`
Porsøgsinsekterne er hunstuefluer på 4-5 dage# Man arbejder ved direkte forstøvning i Keamå' og MarchJs cylinder, idet man som opløsningsmiddel benytter en blanding af acetone 5 (5#) og Isopar L (mineralolieopløsningsmiddel)(benyttet mængde opløsningsmiddel 2 ml pr# sekund). Man benytter 50 insekter pr, dosis. Man foretager kontrol hvert minut indtil 10 minutter og derefter ved 15 minutter, og man bestemmer KT50 ved de gængse metoder.The test insects are female flies of 4-5 days # Work by direct atomization in Keamå 'and MarchJ's cylinder, using as a solvent a mixture of acetone 5 (5 #) and Isopar L (mineral oil solvent) (solvent used 2 ml per # second ). 50 insects are used per dose. Control is performed every minute until 10 minutes and then at 15 minutes, and KT50 is determined by the usual methods.
10 Man konstaterer, at forbindelserne har en god aktivitet, og en af dem, nemlig forbindelsen ifølge eksempel 1, har en bemærkelsesværdig aktivitet, idet dens KT50 er 0,4 minutter, 0,26 minutter og 2,02 minutter ved koncentrationer på henholdsvis lg/liter, 0,5 g/liter og 0,25 g/liter.It is found that the compounds have a good activity and one of them, namely the compound of Example 1, has a remarkable activity, its KT50 being 0.4 minutes, 0.26 minutes and 2.02 minutes at concentrations of 1g, respectively. / liter, 0.5 g / liter and 0.25 g / liter.
15 Eksempel Y. Virkning på Tetran.vchus urticae.Example Y. Effect on Tetran.vchus urticae.
Adulticidt forsøg.Adulticide trial.
Man benytter bønneplanter med 2 blade, som er behandlet med Pisher's pistol i forskellige doser af de undersøgte forbindelser. Efter tørring inficeres disse planker med 25 20 hunner af Tetranychus urticae pr. blad og holdes konstant ved 22-23°C og 60-65# relativ luftfugtighed. Tællingen af levende og døde acarider foretages 24 timer og 48 timer efter behandlingen#Two-leaf bean plants are used, which are treated with Pisher's gun in various doses of the compounds investigated. After drying, these planks are infected with 25 20 females of Tetranychus urticae per year. leaf and kept constant at 22-23 ° C and 60-65 # relative humidity. The count of live and dead acarides is done 24 hours and 48 hours after treatment #
Porbindelserne ifølge eksempel 1-8 har en god adulti-25 cid virkning i dette forsøg.The pore compounds of Examples 1-8 have a good adulticidal effect in this experiment.
Eksempel VI. Undersøgelse af den insekticide virkning på myg af arten Cules pipiens af forbindelsen ifølge eksempel 1 benyttet i form af røgspiral.Example VI. Investigation of the insecticidal effect on mosquitoes of the species Cules pipiens of the compound of Example 1 used in the form of smoke coil.
Neutrale understøtninger for røgspiraler imprægneres 30 med aktivt stof i acetoneopløsning. I en lukket glascylinder på 13,50 dm^ frigør man 20 hunmyg på 4-5 dage og indfører i løbet af 2 minutter en røgspiral, som er antændt ved den ene ende. Man foretager kontrol for knock-down hvert minut og standser forsøget, 5 minutter efter at alle insekterne er slået 35 ned.Neutral supports for smoke coils are impregnated with active substance in acetone solution. In a closed glass cylinder of 13.50 dm ^, 20 female mosquitoes are released in 4-5 days, and within 2 minutes a spiral of smoke which is ignited at one end is introduced. The knock-down check is performed every minute and the test is stopped, 5 minutes after all the insects have been killed.
Resultaterne er som følger: 65 - Ved en dosis på 0,60$ aktivt materiale i forhold til vægten af spiralen er EC50 = 5,42 minutter, og - i denne dosis er den letale virkning 98,3$.The results are as follows: - At a dose of $ 0.60 of active material relative to the weight of the coil, EC50 = 5.42 minutes, and - at this dose, the lethal effect is $ 98.3.
5 Sammenligningsforsøg A. Chokvirkning på stueflue5 Comparative experiment A. Shock effect on housefly
Man går frem som i eksempel IV, idet koncentrationen er 0,25 g/liter.Proceed as in Example IV, the concentration being 0.25 g / liter.
Resultaterne udtrykkes som relativ styrke: 10 Forbindelse ifølge Relativ styrke i forhold eksempel_ til bioalletrin_ 1 6,271 2 2,794 3 1,369 4 3,455 5 2,828 15 6 1,065 7 2,655 8 9,223 9 1,666 14 1,289 17 4,261 21 1,786 2f) 27 4,210 28 13,266 29 7,900 30 2,898 31 10,081 37 2,034 38 2,608 42 2,883 25 44 1,351 47 7,354 48 6,635 50 2,825 58 3,271 62 13,280 64 2,096 65 5,157 66 2,298 70 4,932 75 2,332 35 66 DK 163918j^ \ B. Letal aktivitet på larver afThe results are expressed as relative strength: 10 Compound according to relative strength, for example, to bioalletrine 1 6,271 2 2,794 3 1,369 4 3,455 5 2,828 15 6 1,065 7 2,655 8 9,223 9 1,666 14 1,289 17 4,261 21 1,786 2f) 27 4,210 28 13,266 29 7,900 30 2,898 31 10,081 37 2,034 38 2,608 42 2,883 25 44 1,351 47 7,354 48 6,635 50 2,825 58 3,271 62 13,280 64 2,096 65 5,157 66 2,298 70 4,932 75 2,332 35 66 DK 163918j ^ \ B. Lethal activity of larvae of
Epilachna varivestrisEpilachna varivestris
Man går frem som i eksempel II.Proceed as in Example II.
Resultaterne udtrykkes som relativ styrke: 5 Forbindelse ifølge Relativ styrke i forhold _eksempel_ _til deltamethrin_ 4 9,362 9 1,712 21 2,024 67 1,175 10 15 20 ! i 25 30 35The results are expressed as relative strength: 5 Compound according to relative strength in relation to, for example, _to deltamethrin_ 4 9,362 9 1,712 21 2,024 67 1,175 10 15 20! i 25 30 35
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FR8011569 | 1980-05-23 | ||
FR8011569A FR2482955A1 (en) | 1980-05-23 | 1980-05-23 | NOVEL DERIVATIVES OF CYCLOPROPANE CARBOXYLIC ACID, PROCESS FOR PREPARING THEM AND THEIR APPLICATION TO THE FIGHT AGAINST PARASITES |
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JP (3) | JPS5711943A (en) |
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CA (2) | CA1237433A (en) |
DD (2) | DD159068A5 (en) |
DE (1) | DE3165037D1 (en) |
DK (1) | DK163918C (en) |
EG (1) | EG15439A (en) |
ES (2) | ES8300080A1 (en) |
FI (1) | FI78902C (en) |
FR (1) | FR2482955A1 (en) |
GR (1) | GR81534B (en) |
HU (1) | HU191031B (en) |
IE (1) | IE52150B1 (en) |
IL (1) | IL62914A (en) |
MA (1) | MA19150A1 (en) |
NZ (1) | NZ197175A (en) |
OA (1) | OA06818A (en) |
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Publication number | Priority date | Publication date | Assignee | Title |
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OA06786A (en) * | 1980-04-16 | 1982-12-31 | Roussel Uclaf | New derivatives of cyclopropane acid, their preparation, their application to the fight against parasites of plants and animals, the compositions containing them and the new intermediates obtained. |
FR2491060A1 (en) * | 1980-10-01 | 1982-04-02 | Roussel Uclaf | PYRETHRIC ACID-RELATED CARBOXYLIC CYCLOPROPANIC ACID ESTERS, METHOD FOR THE PREPARATION THEREOF AND THEIR USE IN THE FIGHT AGAINST PESTS |
FR2536389B2 (en) * | 1982-11-22 | 1986-06-27 | Roussel Uclaf | ESTERS OF CYCLOPROPANE CARBOXYLIC ACIDS RELATED TO PYRETRIC ACID, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO PEST CONTROL |
FR2500451B1 (en) * | 1981-02-26 | 1986-09-26 | Roussel Uclaf | ESTERS OF HETEROCYCLIC ALCOHOLS DERIVED FROM THIAZOLE OR THIADIAZOLE, PROCESS FOR THEIR PREPARATION AND PESTICIDE COMPOSITIONS CONTAINING THEM |
FR2517677B1 (en) * | 1981-12-09 | 1986-05-16 | Roussel Uclaf | NOVEL ETHERS WITH ORGANIC REMAINS CONTAINING CHIRAL ATOMS, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO THE SPLITTING OF ALCOHOLS OR CERTAIN HEMIACETAL STRUCTURE COMPOUNDS. |
FR2526018A1 (en) * | 1982-04-30 | 1983-11-04 | Roussel Uclaf | Alpha cyano phenoxy cyclopropane carboxylate(s) - are low toxicity insecticides and acaricides for plants, animals, and buildings |
FR2526017B1 (en) * | 1982-04-30 | 1985-10-11 | Roussel Uclaf | ESTER OF CYCLOPROPANE CARBOXYLIC ACID AND CYANO (4-FLUORO 3-PHENOXYPHENYL) METHYLIC ALCOHOL (S), PREPARATION METHOD THEREOF AND PESTICIDE COMPOSITIONS CONTAINING THE SAME |
US4505738A (en) * | 1982-05-10 | 1985-03-19 | Ciba-Geigy Corporation | Halovinyl-3,3-dimethylcyclopropanecarboxylic acid pyronyl esters useful for the protection of cultivated plants against the harmful effects of herbicides |
FR2533416B1 (en) * | 1982-09-29 | 1988-09-02 | Roussel Uclaf | NOVEL PESTICIDE COMPOSITIONS CONTAINING A PHOTOSTABILIZER |
FR2539411B2 (en) * | 1983-01-17 | 1986-04-25 | Roussel Uclaf | NOVEL DERIVATIVES OF CYCLOPROPANE CARBOXYLIC ACID, THEIR PREPARATION METHOD, THEIR APPLICATION TO THE CONTROL OF PESTS |
FR2574403B1 (en) * | 1984-12-06 | 1987-01-30 | Roussel Uclaf | NOVEL ESTERS DERIVED FROM CYCLOPROPANE CARBOXYLIC ACID AND (R) 2- (6-PHENOXY PYRIDYL) ETHANOL, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO PEST CONTROL |
FR2586675B1 (en) * | 1985-08-27 | 1987-12-11 | Roussel Uclaf | NOVEL ESTERS OF CYCLOPROPANE CARBOXYLIC ACID AND 2,3 DIHYDRO-4-PHENYL-IH-INDEN-2-OL, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO PEST CONTROL |
FR2610624B1 (en) * | 1987-02-06 | 1989-06-09 | Roussel Uclaf | NOVEL ESTERS OF PYRETHRIC ACID-LIKE CYCLOPROPANECARBOXYLIC ACIDS, THEIR PREPARATION PROCESS AND THEIR APPLICATION TO PEST CONTROL |
JP2570388B2 (en) * | 1988-06-10 | 1997-01-08 | 住友化学工業株式会社 | Carboxylic acid esters and their use as insecticides |
US5055491A (en) * | 1989-04-10 | 1991-10-08 | Sumitomo Chemical Company, Limited | Carboxylic acid esters, methods for producing them and insecticides and/or acaricides containing them as an active ingredient |
FR2678611B1 (en) * | 1991-07-04 | 1995-01-20 | Roussel Uclaf | NOVEL PYRETHRINOUID ESTERS OF ALCOHOL 1,3,4,5,6,7-HEXAHYDRO 1,3-DIOXO-2H-ISOINDOL-2-YL-METHYLIQUE, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS PESTICIDES. |
FR2678609B1 (en) * | 1991-07-04 | 1994-08-26 | Roussel Uclaf | NOVEL PYRETHRINOUID ESTERS OF THE ALCOHOL 4-AMINO 2,3,5,6-TETRAFLUOROPHENYL METHYLIQUE, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS PESTICIDES. |
FR2687149B1 (en) * | 1992-02-12 | 1995-11-03 | Roussel Uclaf | NOVEL PYRETHRINOUID ESTERS DERIVED FROM THIAZOLIC ALCOHOLS, THEIR PREPARATION PROCESS AND THEIR APPLICATION AS PESTICIDES. |
DE69618096T2 (en) * | 1995-02-07 | 2002-07-18 | Dainihon Jochugiku Co., Ltd. | NEW CARBONIC ACID DERIVATIVES, METHOD FOR THE PRODUCTION AND INSECTICIDES CONTAINING THESE COMPOUNDS |
US5852048A (en) * | 1995-03-01 | 1998-12-22 | Sumitomo Chemical Company, Limited | Ester compound and a pesticidal agent containing the same as an active ingredient |
JP4488765B2 (en) * | 2004-02-26 | 2010-06-23 | 大日本除蟲菊株式会社 | Aerosol insecticide |
TW200716517A (en) | 2005-04-29 | 2007-05-01 | Wyeth Corp | Process for preparing 3,3-disubstituted oxindoles and thio-oxindoles |
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JPS515450B1 (en) * | 1971-06-29 | 1976-02-20 | ||
DE2326077C2 (en) * | 1972-05-25 | 1985-12-12 | National Research Development Corp., London | Unsaturated cyclopropanecarboxylic acids and their derivatives, their preparation and insecticides containing them |
CH589408A5 (en) * | 1973-04-18 | 1977-07-15 | Ciba Geigy Ag | |
DE2706222A1 (en) * | 1976-02-16 | 1977-08-18 | Ciba Geigy Ag | CYCLOPROPANCARBONIC ACID ESTERS, METHOD OF MANUFACTURING AND USING them |
US4242357A (en) * | 1976-04-09 | 1980-12-30 | Bayer Aktiengesellschaft | Carboxylic acid esters for combating pests |
CA1117673A (en) * | 1977-12-29 | 1982-02-02 | Hajime Shichijo | Tuning apparatus |
HU176939B (en) * | 1978-02-23 | 1981-06-28 | Chinoin Gyogyszer Es Vegyeszet | Process for pproducing derivatives of esters of chrisanthemic acid |
HU176938B (en) * | 1978-02-23 | 1981-06-28 | Chinoin Gyogyszer Es Vegyeszet | Process for preparing new chrysanthemic acid ester derivatives |
-
1980
- 1980-05-23 FR FR8011569A patent/FR2482955A1/en active Granted
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1981
- 1981-05-15 SU SU813284396A patent/SU1342408A3/en active
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- 1981-05-20 EG EG81281A patent/EG15439A/en active
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- 1981-05-20 IL IL62914A patent/IL62914A/en unknown
- 1981-05-20 MA MA19359A patent/MA19150A1/en unknown
- 1981-05-21 FI FI811566A patent/FI78902C/en not_active IP Right Cessation
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- 1981-05-22 CA CA000378108A patent/CA1237433A/en not_active Expired
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1982
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1984
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